Methods of reducing risk of infection from pathogens

ABSTRACT

Prophylactic treatment methods are provided for protection of individuals and/or populations against infection from airborne pathogens. In particular, prophylactic treatment methods are provided comprising administering a sodium channel blocker or pharmaceutically acceptable salts thereof to one or more members of a population at risk of exposure to or already exposed to one or more airborne pathogens, either from natural sources or from intentional release of pathogens into the environment.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.60/496,481, filed Aug. 20, 2003, 60/495,725, filed Aug. 19, 2003,60/495,712, filed Aug. 19, 2003 and 60/495,720, filed Aug. 19, 2003,each of which is incorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

The present invention relates to the use of sodium channel blockers forprophylactic, post-exposure prophylactic, preventive or therapeutictreatment against diseases or conditions caused by pathogens,particularly pathogens which may be used in bioterrorism.

2. Description of the Related Art

In recent years, a variety of research programs and biodefense measureshave been put into place to deal with concerns about the use ofbiological agents in acts of terrorism. These measures are intended toaddress concerns regarding bioterrorism or the use of microorganisms orbiological toxins to kill people, spread fear, and disrupt society. Forexample, the National Institute of Allergy and Infectious Diseases(NIAID) has developed a Strategic Plan for Biodefense Research whichoutlines plans for addressing research needs in the broad area ofbioterrorism and emerging and reemerging infectious diseases. Accordingto the plan, the deliberate exposure of the civilian population of theUnited States to Bacillus anthracis spores revealed a gap in thenation's overall preparedness against bioterrorism. Moreover, the reportdetails that these attacks uncovered an unmet need for tests to rapidlydiagnose, vaccines and immunotherapies to prevent, and drugs andbiologics to cure disease caused by agents of bioterrorism.

Much of the focus of the various research efforts has been directed tostudying the biology of the pathogens identified as potentiallydangerous as bioterrorism agents, studying the host response againstsuch agents, developing vaccines against infectious diseases, evaluatingthe therapeutics currently available and under investigation againstsuch agents, and developing diagnostics to identify signs and symptomsof threatening agents. Such efforts are laudable but, given the largenumber of pathogens which have been identified as potentially availablefor bioterrorism, these efforts have not yet been able to providesatisfactory responses for all possible bioterrorism threats.Additionally, many of the pathogens identified as potentially dangerousas agents of bioterrorism do not provide adequate economic incentivesfor the development of therapeutic or preventive measures by industry.Moreover, even if preventive measures such as vaccines were availablefor each pathogen which may be used in bioterrorism, the cost ofadministering all such vaccines to the general population isprohibitive.

Until convenient and effective treatments are available against everybioterrorism threat, there exists a strong need for preventative,prophylactic or therapeutic treatments which can prevent or reduce therisk of infection from pathogenic agents.

BRIEF SUMMARY

The present invention provides such methods of prophylactic treatment.In one embodiment, a prophylactic treatment method is providedcomprising administering a prophylactically effective amount of a sodiumchannel blocker according to Formula I:

wherein

-   -   X is hydrogen, halogen, trifluoromethyl, lower alkyl,        unsubstituted or substituted phenyl, lower alkyl-thio,        phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower        alkyl-sulfonyl;    -   Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower        alkyl-thio, halogen, lower alkyl, unsubstituted or substituted        mononuclear aryl, or —N(R²)₂;    -   R¹ is hydrogen or lower alkyl;    -   each R² is, independently, —R⁷, —(CH₂)_(m)—OR⁸,        —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —(CH₂)_(n)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-Z_(g)-R⁷,        —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,        or    -   R³ and R⁴ are each, independently, hydrogen, a group represented        by formula (A), lower alkyl, hydroxy lower alkyl, phenyl,        phenyl-lower alkyl, (halophenyl)-lower alkyl,        lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl,        naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso        that at least one of R³ and R⁴ is a group represented by formula        (A):        wherein    -   each R^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸,        —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,        —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—O—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   each o is, independently, an integer from 0 to 10;    -   each p is an integer from 0 to 10;    -   with the proviso that the sum of o and p in each contiguous        chain is from 1 to 10;    -   each x is, independently, O, NR¹⁰, C(═O), CHOH, C(═N—R¹⁰),        CHNR⁷R¹⁰, or represents a single bond;    -   wherein each R⁵ is, independently,    -   Link —(CH₂)_(n)—CAP, Link —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂CH₂O)_(m)—CH₂—CAP, Link —(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link        —(CH₂)_(n)-(Z)_(g)-CAP, Link —(CH₂)_(n)(Z)_(g)-(CH₂)_(m)—CAP ,        Link —(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link NH—C(═O)NH(CH₂)_(m)—CAP,        Link —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰R¹⁰, Link        —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link        —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link —(CH₂)_(m)—C(═O)NR¹²R¹², Link        —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP, Link        -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP;    -   wherein Link is, independently,    -   —O—, (CH₂)_(n)—, —O(CH₂)_(m)—, —NR¹³—C(═O)—NR¹³,        —NR¹³C(═O)—(CH₂)_(m)—, —C(═O)NR¹³—(CH₂)_(m),        —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—, SO₂NR⁷—, SO₂NR¹⁰—,        -Het-;    -   wherein each CAP is, independently, thiazolidinedione,        oxazolidinedione, heteroaryl-C(═O)NR¹³R¹³, heteroaryl-CAP, —CN,        —O—C(═S)NR¹³R¹³, -Z_(g)R¹³, —CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³),        —C(═O)OAr, —C(═O)NR¹³Ar, imidazoline, tetrazole, tetrazole        amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³, cyclic sugars        and oligosaccharides, including cyclic amino sugars and        oligosaccharides,    -   wherein Ar is, independently, phenyl; substituted phenyl,        wherein said substituent is 1-3 groups selected, independently,        from OH, OCH₃, NR¹³R¹³, Cl, F, CH₃; heteroaryl, e.g., pyridine,        pyrazine, tinazine, furyl, furfuryl-, thienyl, tetrazole,        thiazolidinedione and imidazoyl (        ) and other heteroaromatic ring systems as defined below;    -   wherein heteroaryl is selected from one of the following        heteroaromatic systems:    -   Pyrrole, Furan, Thiophene, Pyridine, Quinoline, Indole, Adenine,        Pyrazole, Imidazole, Thiazole, Isoxazole, Indole, Benzimidazole,        Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,        Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine,        Cinnoline, Phthalazine, Quinazoline, Quinoxaline and Pterdine;    -   each R⁶ is, independently, —R⁷, —OR⁷, —OR¹¹, —N(R⁷)₂,        —(CH₂)_(m)—OR⁸, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰,        —O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   where when two R⁶ are —OR¹¹ and are located adjacent to each        other on a phenyl ring, the alkyl moieties of the two R⁶ may be        bonded together to form a methylenedioxy group;    -   with the proviso that when at least two —CH₂OR⁸ are located        adjacent to each other, the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,    -   each R⁷ is, independently, hydrogen lower alkyl, phenyl,        substituted phenyl or —CH₂(CHOR)⁸ _(m)—R¹⁰;    -   each R⁸ is, independently, hydrogen, lower alkyl, —C(═O)—R¹¹,        glucuronide, 2-tetrahydropyranyl, or    -   each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or        —C(═O)R¹³;    -   each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³,    -   —C(═O)R¹³, or —CH₂)_(m)—(CHOH)_(n)—CH₂OH;    -   each Z is, independently, CHOH, C(═O), —(CH₂)_(n)—CHNR¹³R¹³,        C═NR¹³, or NR¹³;    -   each R¹¹ is, independently, lower alkyl;    -   each R¹² is independently, —SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³,        —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH;    -   each R¹³ is, independently, hydrogen, R⁷, R¹⁰,        —(CH₂)_(m)—NR¹³R¹³,    -   with the proviso that NR¹³R¹³ can be joined on itself to form a        ring comprising one of the following:    -   each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—,        —SO₂NR¹³—, —NHSO₂—, —NR¹³CO—, —CONR¹³—;    -   each g is, independently, an integer from 1 to 6;    -   each m is, independently, an integer from 1 to 7;    -   each n is, independently, an integer from 0 to 7;    -   each Q is, independently, C—R⁵, C—R⁶, or a nitrogen atom,        wherein atom wherein at    -   most three Q in a ring are nitrogen atoms;    -   each V is, independently, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(m)—NR⁷R⁷,        —(CH₂)_(m)—    -   with the proviso that when V is attached directly to a nitrogen        atom, then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂;    -   wherein for any of the above compounds when two —CH₂OR⁸ groups        are located 1,2- or 1,3- with respect to each other the R⁸        groups may be joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane, or a pharmaceutically acceptable        salt thereof to an individual in need of prophylactic treatment        against infection from one or more airborne pathogens.

In another embodiment, a prophylactic treatment method is providedcomprising administering a prophylactically effective amount of a sodiumchannel blocker according to Formula II:

where

-   -   X is hydrogen, halogen, trifluoromethyl, lower alkyl,        unsubstituted or substituted phenyl, lower alkyl-thio,        phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower        alkyl-sulfonyl;    -   Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower        alkyl-thio, halogen, lower alkyl, unsubstituted or substituted        mononuclear aryl, or —N(R²)₂;    -   R¹ is hydrogen or lower alkyl;    -   each R² is, independently, —R⁷, —(CH₂)_(m)—OR⁸,        —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —(CH₂)_(n)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-Z_(g)-R⁷,        —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,        or    -   R^(3′) and R^(4′) are each, independently, hydrogen, a group        represented by formula (A′), lower alkyl, hydroxy lower alkyl,        phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl,        lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl,        naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso        that at least one of R^(3′) and R^(4′) is a group represented by        formula (A′):        —(C(R^(L))₂)_(O)-x-(C(R^(L))₂)_(P)-CR^(5′)R^(6′)R^(6′)  (A′)        where    -   each R^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸,        —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,        —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR₈)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   each o is, independently, an integer from 0 to 10;    -   each p is an integer from 0 to 10;    -   with the proviso that the sum of o and p in each contiguous        chain is from 1 to 10;    -   each x is, independently, O, NR¹⁰, C(═O), CHOH, C(═N—R¹⁰),        CHNR⁷R¹⁰, or represents a single bond;    -   each R^(5′) is, independently, —O—(CH₂)_(m)—OR⁸,        —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,        —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   each R^(5′) is also, independently, —(CH₂)_(n)—NR¹²R¹²,        —O—(CH₂)_(m)—NR¹²R¹², —O—(CH₂)_(n)—NR¹²R¹²,        —O—(CH₂)_(m)-(Z)_(g)R¹², —(CH₂)_(n)NR¹¹R¹¹, —O—(CH₂)_(m)NR¹¹R¹¹,        —(CH₂)_(n)—N^(⊕)—(R¹¹)₃, —O—(CH₂)_(m)—N^(⊕)—(R¹¹)₃,        —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,        —O—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,        —(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹², —O—(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,        —(CH₂)_(n)—(C═O)NR¹²R¹², —O—(CH₂)_(m)—(C═O)NR¹²R¹²,        —O—(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        —(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹⁰-(Z)_(g)-R¹⁰,        —(CH₂)_(n)NR¹⁰—O(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        —O(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        -(Het)-(CH₂)_(m)—OR⁸, -(Het)-(CH₂)_(m)—NR⁷R¹⁰,        -(Het)-(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        -(Het)-(CH₂CH₂O)_(m)—R⁸, -(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        -(Het)-(CH₂)_(m)—C(═O)NR⁷R¹⁰, -(Het)-(CH₂)_(m)-(Z)_(g)-R⁷,        -(Het)-(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        -(Het)-(CH₂)_(m)—CO₂R⁷, -(Het)-(CH₂)_(m)—NR¹²R¹²,        -(Het)-(CH₂)_(n)—NR¹²R¹², -(Het)-(CH₂)_(m)-(Z)_(g)R¹²,        -(Het)-(CH₂)_(m)NR¹¹R¹¹, -(Het)-(CH₂)_(m)—N^(⊕)—(R¹¹)₃,        -(Het)-(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰OR¹⁰,        —(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,        -(Het)-(CH₂)_(m)—(C═O)NR¹²R²,        -(Het)-(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        -(Het)-(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,    -   wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,    -   —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at        least two —CH₂OR⁸ are located adjacent to each other and the R⁸        groups are joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane,    -   —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at        least two —CH₂OR⁸ are located adjacent to each other and the R⁸        groups are joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane,    -   —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso        that at least two —CH₂OR⁸ are located adjacent to each other and        the R⁸ groups are joined to form a cyclic mono- or        di-substituted 1,3-dioxane or 1,3-dioxolane, or    -   —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)CH₂OR⁸, with the proviso        that at least two —CH₂OR⁸ are located adjacent to each other and        the R⁸ groups are joined to form a cyclic mono- or        di-substituted 1,3-dioxane or 1,3-dioxolane;    -   wherein each R^(5′) is also, independently,    -   Link —(CH₂)_(n)—CAP, Link —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂CH₂O)_(m)—CH₂—CAP, Link —(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link        —(CH₂)_(n)-(Z)_(g)-CAP, Link —(CH₂)_(n)(Z)_(g)-(CH₂)_(m)—CAP,        Link —(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link        NH—C(═O)—NH—(CH₂)_(m)—CAP, Link        —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰R¹⁰, Link        —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link        —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link —(CH₂)_(m)—C(═O)NR¹²R¹², Link        —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP, Link        -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP;    -   wherein Link is, independently, —O—, (CH₂)_(n)—, —O(CH₂)_(m)—,        —NR¹³—C(═O)—NR¹³, —NR¹³—C(═O)—(CH₂)_(m)—, —C(═O)NR¹³—(CH₂)_(m),        —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—, SO₂NR⁷—, SO₂NR¹⁰—,        -Het-;    -   wherein each CAP is, independently, thiazolidinedione,        oxazolidinedione, heteroaryl-C(═O)NR¹³R¹³ , heteroaryl-CAP, —CN,        —O—C(═S)NR¹³R¹³, -Z_(g)R¹³, —CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³),        —C(═O)OAr, —C(═O)NR¹³Ar, imidazoline, tetrazole, tetrazole        amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³, cyclic sugars        and oligosaccharides, including cyclic amino sugars and        oligosaccharides,    -   wherein Ar is, independently, phenyl; substituted phenyl,        wherein said substituent is 1-3 groups selected, independently,        from OH, OCH₃, NR¹³R¹³, Cl, F, CH₃; heteroaryl, e.g., pyridine,        pyrazine, tinazine, furyl, furfuryl-, thienyl, tetrazole,        thiazolidinedione and imidazoyl (        ) and other heteroaromatic ring systems as defined below;    -   wherein heteroaryl is selected from one of the following        heteroaromatic systems:    -   Pyrrole, Furan, Thiophene, Pyridine, Quinoline, Indole, Adenine,        Pyrazole, Imidazole, Thiazole, Isoxazole, Indole, Benzimidazole,        Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,        Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine,        Cinnoline, Phthalazine, Quinazoline, Quinoxaline and Pterdine;    -   wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,

each R^(6′) is, independently, —R^(5′), —R⁷, —OR⁸, —N(R⁷)₂,—(CH₂)_(m)—OR⁸, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(m)—NR⁷R¹⁰,—O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—OC₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

-   -   wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;    -   each R⁷ is, independently, hydrogen lower alkyl, phenyl,        substituted phenyl or —CH₂(CHOR)⁸ _(m)—R¹⁰;    -   each R⁸ is, independently, hydrogen, lower alkyl, —C(═O)—R¹¹,        glucuronide, 2-tetrahydropyranyl, or

each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or—C(═O)R¹³;

-   -   each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³R—C(═O)NR¹³R¹³,        —C(═O)R¹³, or —(CH₂)_(m)—(CHOH)_(n)—CH₂OH;    -   each Z is, independently, CHOH, C(═O), —(CH₂)_(n)—, CHNR¹³R¹³,        C═NR¹³, or NR¹³;    -   each R¹¹ is, independently, lower alkyl;    -   each R¹² is independently, —SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³,        —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH;    -   each R¹³ is, independently, hydrogen, R⁷, R¹⁰,        —(CH₂)_(m)—NR¹³R¹³,    -   with the proviso that NR¹³R¹³ can be joined on itself to form a        ring comprising one of the following:    -   each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—,        —SO₂NR¹³—, —NHSO₂—, —NR¹³CO—, —CONR¹³—;    -   each g is, independently, an integer from 1 to 6;    -   each m is, independently, an integer from 1 to 7;    -   each n is, independently, an integer from 0 to 7;    -   each V is, independently, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(m)—NR⁷R⁷,        —(CH₂)_(m)—    -   with the proviso that when V is attached directly to a nitrogen        atom, then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂;    -   wherein for any of the above compounds when two —CH₂OR⁸ groups        are located 1,2- or 1,3- with respect to each other the R⁸        groups may be joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane; or a pharmaceutically acceptable        salt thereof to an individual in need of prophylactic treatment        against infection from one or more airborne pathogens.

In another embodiment, a prophylactic treatment method is providedcomprising administering a prophylactically effective amount of a sodiumchannel blocker according to Formula III:

where

-   -   X is hydrogen, halogen, trifluoromethyl, lower alkyl,        unsubstituted or substituted phenyl, lower alkyl-thio,        phenyl-lower alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower        alkyl-sulfonyl;    -   Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower        alkyl-thio, halogen, lower alkyl, unsubstituted or substituted        mononuclear aryl, or —N(R²)₂;    -   R¹ is hydrogen or lower alkyl;    -   each R² is, independently, —R⁷, —(CH₂)_(m)—OR⁸,        —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —(CH₂)_(n)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-Z_(g)-R⁷,        —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,        or    -   R^(3″) and R^(4″) are each, independently, hydrogen, a group        represented by formula (A″), lower alkyl, hydroxy lower alkyl,        phenyl, phenyl-lower alkyl, (halophenyl)-lower alkyl,        lower-(alkylphenylalkyl), lower (alkoxyphenyl)-lower alkyl,        naphthyl-lower alkyl, or pyridyl-lower alkyl, with the proviso        that at least one of R^(3′) and R^(4″) is a group represented by        formula (A″):        where    -   each R^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸,        —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,        —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   each o is, independently, an integer from 0 to 10;    -   each p is an integer from 0 to 10;    -   with the proviso that the sum of o and p in each contiguous        chain is from 1 to 10;    -   each x is, independently, O, NR¹⁰, C(═O), CHOH, C(═N—R¹⁰),    -   CHNR⁷R¹⁰, or represents a single bond;    -   each R^(5′) is, independently, independently, —O—(CH₂)_(m)—OR⁸,        —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,        —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   each R^(5′) is also, independently, —(CH₂)_(n)—NR¹²R¹²,        —O—(CH₂)_(m)—NR¹²R¹², —O—(CH₂)_(n)—NR¹²R¹²,        —O—(CH₂)_(m)-(Z)_(g)R¹², —(CH₂)_(n)NR¹¹R¹¹, —O—(CH₂)_(m)NR¹¹R¹¹,        —(CH₂)_(n)—N^(⊕)—(R¹¹)₃, —O—(CH₂)_(m)—N^(⊕)—(R¹¹)₃,        —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)—NR¹⁰OR¹⁰,        —O—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,        —(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹², —O—(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,        —(CH₂)_(n)—(C═O)NR¹²R¹², —O—(CH₂)_(m)—(C═O)NR¹²R¹²,        —O—(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        —(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹⁰-(Z)_(g)-R¹⁰,        —(CH₂)_(n)NR¹⁰—O(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        —O(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g-R) ¹⁰,        -(Het)-(CH₂)_(m)—OR⁸, -(Het)-(CH₂)_(m)—NR⁷R¹⁰,        -(Het)-(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        -(Het)-(CH₂CH₂O)_(m)—R⁸, -(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        -(Het)-(CH₂)_(m)—C(═O)NR⁷R¹⁰, -(Het)-(CH₂)_(m)-(Z)_(g)-R⁷,        -(Het)-(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        -(Het)-(CH₂)_(m)—CO₂R⁷, -(Het)-(CH₂)m-NR¹²R¹²,        -(Het)-(CH₂)_(n)—NR¹²R¹², -(Het)-(CH₂)_(m)-(Z)_(g)R¹²,        -(Het)-(CH₂)_(m)NR¹¹R¹¹, -(Het)-(CH₂)_(m)—N^(⊕)—(R¹¹)₃,        -(Het)-(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰OR¹⁰,        -(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,        -(Het)-(CH₂)_(m)—(C═O)NR¹²R¹²,        -(Het)-(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,        -(Het)-(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,    -   wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,    -   —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at        least two —CH₂OR⁸ are located adjacent to each other and the R⁸        groups are joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane,    -   —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂0R⁸, with the proviso that at        least two —CH₂OR⁸ are located adjacent to each other and the R⁸        groups are joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane,    -   —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso        that at least two —CH₂OR⁸ are located adjacent to each other and        the R⁸ groups are joined to form a cyclic mono- or        di-substituted 1,3-dioxane or 1,3-dioxolane, or    -   —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso        that at least two —CH₂OR⁸ are located adjacent to each other and        the R⁸ groups are joined to form a cyclic mono- or        di-substituted 1,3-dioxane or 1,3-dioxolane;    -   wherein each R^(5′) is also, independently,    -   Link —(CH₂)_(n)—CAP, Link —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂CH₂O)_(m)—CH₂—CAP, Link —(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link        —(CH₂)_(n)-(Z)_(g)-CAP, Link —(CH₂)_(n)(Z)_(g)-(CH₂)_(m)—CAP,        Link —(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link        —(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link        —(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link        NH—C(═O)—NH—(CH₂)_(m)—CAP, Link        —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰OR¹⁰, Link        —(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link        —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link —(CH₂)_(m)—C(═O)NR¹²R¹², Link        —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP, Link        -Z_(g)-(CH₂)m-Het-(CH₂)_(m)—CAP;    -   wherein Link is, independently,    -   —O—, (CH₂)_(n)—, —O(CH₂)_(m), —NR¹³—C(═O)—NR¹³,        —NR¹³—C(═O)—(CH₂)_(m)—, —C(═O)NR¹³—(CH₂)_(m),        —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—, SO₂NR⁷—, SO₂NR¹⁰—,        -Het-;    -   wherein each CAP is, independently, thiazolidinedione,        oxazolidinedione, heteroaryl-C(═O)NR²³R¹³, heteroaryl-CAP, —CN,        —O—C(═S)NR¹³R¹³, -Z_(g)R¹³, —CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³),        —C(═O)NR¹³Ar, imidazoline, tetrazole, tetrazole amide,        —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³, cyclic sugars and        oligosaccharides, including cyclic amino sugars and        oligosaccharides,    -   wherein Ar is, independently, phenyl; Substituted phenyl,        wherein said substituent is 1-3 groups selected, independently,        from OH, OCH₃, NR¹³R¹³, Cl, F, CH₃; heteroaryl, e.g., pyridine,        pyrazine, tinazine, furyl, furfuryl-, thienyl, tetrazole,        thiazolidinedione and imidazoyl (        ) and other heteroaromatic ring systems as defined below;    -   wherein heteroaryl is selected from one of the following        heteroaromatic systems:    -   Pyrrole, Furan, Thiophene, Pyridine, Quinoline, Indole, Adenine,        Pyrazole, Imidazole, Thiazole, Isoxazole, Indole, Benzimidazole,        Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,        Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine,        Cinnoline, Phthalazine, Quinazoline, Quinoxaline and Pterdine;    -   wherein when two —(CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;    -   each R^(6′) is, independently, —R^(5′), —R⁷, —OR⁸, —N(R⁷)₂,        —(CH₂)_(m)—OR⁸, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰,        —O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide,        —O-glucose,    -   wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3- with        respect to each other the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;    -   each R⁷ is, independently, hydrogen lower alkyl, phenyl,        substituted phenyl or —CH₂(CHOR)⁸ _(m)—R¹⁰;    -   each R⁸ is, independently, hydrogen, lower alkyl, —C(═O)—R¹¹,        glucuronide, 2-tetrahydropyranyl, or    -   each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or    -   each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³,        C(═O)R¹³, or —(CH₂)_(m)—(CHOH)_(n)—CH₂OH;    -   each Z is, independently, CHOH, C(═O), —(CH₂)_(n)—, CHNR¹³R¹³,        C═NR¹³, or NR¹³;    -   each R¹¹ is, independently, lower alkyl;    -   each R¹² is independently, —SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³,        —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH;    -   each R¹³ is, independently, hydrogen, R⁷, R¹⁰,        —(CH₂)_(m)—NR¹³R¹³,    -   with the proviso that NR¹³R¹³ can be joined on itself to form a        ring comprising one of the following:    -   each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—,        —SO₂NR¹³—, —NHSO₂—, —NR¹³CO—, —CONR¹³—;    -   each g is, independently, an integer from 1 to 6;    -   each m is, independently, an integer from 1 to 7;    -   each n is, independently, an integer from 0 to 7;    -   each Q′ is, independently, —CR^(6′)R^(5′), —CR^(6′)R^(6′), N,        —NR₃, —S—, —SO—, or —SO₂—;    -   wherein at most three Q′ in a ring contain a heteroatom and at        least one Q′ must be —CR^(5′)R^(6′) or NR^(5′);    -   each V is, independently, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(m)—NR⁷R⁷,        —(CH₂)_(m)—    -   with the proviso that when V is attached directly to a nitrogen        atom, then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂;    -   wherein for any of the above compounds when two —CH₂OR⁸ groups        are located 1,2- or 1,3- with respect to each other the R⁸        groups may be joined to form a cyclic mono- or di-substituted        1,3-dioxane or 1,3-dioxolane;    -   or a pharmaceutically acceptable salt thereof, to an individual        in need of prophylactic treatment against infection from one or        more airborne pathogens.

In another embodiment, a prophylactic treatment method is provided forreducing the risk of infection from an airborne pathogen which can causea disease in a human, said method comprising administering an effectiveamount of a sodium channel blocker of Formula I, II or III, or apharmaceutically acceptable salt thereof, to the lungs of the human whomay be at risk of infection from the airborne pathogen but isasymptomatic for the disease, wherein the effective amount of a sodiumchannel blocker or a pharmaceutically acceptable salt is sufficient toreduce the risk of infection in the human.

In another embodiment, a post-exposure prophylactic treatment ortherapeutic treatment method is provided for treating infection from anairborne pathogen comprising administering an effective amount of asodium channel blocker of Formula I, II or III, or a pharmaceuticallyacceptable salt thereof to the lungs of an individual in need of suchtreatment against infection from an airborne pathogen.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The prophylactic or therapeutic treatment methods of the presentinvention may be used in situations where a segment of the populationhas been, or is believed to have been, exposed to one or more airbornepathogens. The prophylactic or therapeutic treatment methods mayadditionally be used in situations of ongoing risk of exposure to orinfection from airborne pathogens. Such situations may arise due tonaturally occurring pathogens or may arise due to a bioterrorism eventwherein a segment of the population is intentionally exposed to one ormore pathogens. The individuals or portion of the population believed tobe at risk from infection can be treated according to the methodsdisclosed herein. Such treatment preferably will commence at theearliest possible time, either prior to exposure if imminent exposure toa pathogen is anticipated or possible or after the actual or suspectedexposure. Typically, the prophylactic treatment methods will be used onhumans asymptomatic for the disease for which the human is believed tobe at risk. The term “asymptomatic” as used herein means not exhibitingmedically recognized symptoms of the disease, not yet suffering frominfection or disease from exposure to the airborne pathogens, or not yettesting positive for a disease. The treatment methods may involvepost-exposure prophylactic or therapeutic treatment, as needed.

Many of the pathogenic agents identified by NIAID have been or arecapable of being aerosolized such that they may enter the body throughthe mouth or nose, moving into the bodily airways and lungs. These areasof the body have mucosal surfaces which naturally serve, in part, todefend against foreign agents entering the body. The mucosal surfaces atthe interface between the environment and the body have evolved a numberof “innate defense”, i.e., protective mechanisms. A principal form ofsuch innate defense is to cleanse these surfaces with liquid. Typically,the quantity of the liquid layer on a mucosal surface reflects thebalance between epithelial liquid secretion, often reflecting anion (Cl⁻and/or HCO₃ ⁻) secretion coupled with water (and a cation counter-ion),and epithelial liquid absorption, often reflecting Na⁺ absorption,coupled with water and counter anion (Cl⁻ and/or HCO₃ ⁻).

R. C. Boucher, in U.S. Pat. No. 6,264,975, describes methods ofhydrating mucosal surfaces, particularly nasal airway surfaces, byadministration of pyrazinoylguanidine sodium channel blockers. Thesecompounds, typified by amiloride, benzamil and phenamil, are effectivefor hydration of the mucosal surfaces. U.S. Pat. No. 5,656,256,describes methods of hydrating mucous secretions in the lungs byadministration of benzamil or phenamil, for example, to treat diseasessuch as cystic fibrosis and chronic bronchitis. U.S. Pat. No. 5,725,842is directed to methods of removing retained mucus secretions from thelungs by administration of amiloride.

It has now been discovered that certain sodium channel blockers whichare classes of pyrazinoylguanidine compounds described and exemplifiedherein as Formulas I, II and III, and in U.S. Provisional PatentApplications 60/495,725, filed Aug. 19, 2003, 60/495,712, filed Aug. 19,2003 and 60/495,720, filed Aug. 19, 2003, incorporated herein in theirentirety, may be used in prophylactic treatment methods to protecthumans in whole or in part, against the risk of infection from pathogenswhich may or may not have been purposely introduced into theenvironment, typically into the air, of a populated area. Such treatmentmay be effectively used to protect those who may have been exposed wherea vaccine is not available or has not been provided to the populationexposed and/or in situations where treatments for the infectionresulting from the pathogen to which a population has been subjected areinsufficient or unavailable altogether.

Without being bound by any theory, it is believed that the sodiumchannel blockers disclosed herein surprisingly may be used onsubstantially normal or healthy lung tissue to prevent or reduce theuptake of airborne pathogens and/or to clear the lungs of all or atleast a portion of such pathogens. Preferably, the sodium channelblockers will prevent or reduce the viral or bacterial uptake ofairborne pathogens. The ability of sodium channel blockers to hydratemucosal surfaces is believed to function to first hydrate lung mucoussecretions, including mucous containing the airborne pathogens to whichthe human has been subjected, and then facilitate the removal of thelung mucous secretions from the body. By functioning to remove the lungmucous secretions from the body, the sodium channel blocker thusprevents or, at least, reduces the risk of infection from thepathogen(s) inhaled or brought into the body through a bodily airway.

The present invention is concerned primarily with the prophylactic, postexposure, rescue and therapeutic treatment of human subjects, but mayalso be employed for the treatment of other mammalian subjects, such asdogs and cats, for veterinary purposes, and to the extent the mammalsare at risk of infection or disease from airborne pathogens.

The term “airway” as used herein refers to all airways in therespiratory system such as those accessible from the mouth or nose,including below the larynx and in the lungs, as well as air passages inthe head, including the sinuses, in the region above the larynx.

The terms “pathogen” and “pathogenic agent” are interchangeable and, asused herein, means any agent that can cause disease or a toxic substanceproduced by a pathogen that causes disease. Typically, the pathogenicagent will be a living organism that can cause disease. By way ofexample, a pathogen may be any microorganism such as bacterium,protozoan or virus that can cause disease.

The term “airborne pathogen” means any pathogen which is capable ofbeing transmitted through the air and includes pathogens which travelthrough air by way of a carrier material and pathogens eitherartificially aerosolized or naturally occurring in the air.

The term “prophylactic” as used herein means the prevention ofinfection, the delay of infection, the inhibition of infection and/orthe reduction of the risk of infection from pathogens and includes pre-and post-exposure to pathogens. The prophylactic effect may, inter alia,involve a reduction in the ability of pathogens to enter the body, ormay involve the removal of all or a portion of pathogens which reachairways and airway surfaces in the body from the body prior to thepathogens initiating or causing infection or disease. The airways fromwhich pathogens may be removed, in whole or part, include all bodilyairways and airway surfaces with mucosal surfaces, including airwaysurfaces in the lungs.

The term “therapeutic” as used herein means to alleviate disease orinfection from pathogens.

The compounds useful in this invention include sodium channel blockerssuch as those represented by Formulas I, II and III. The sodium channelblockers disclosed may be prepared by the procedures described herein,in combination with procedures known to those skilled in the art.

The term sodium channel blocker as used herein includes the free baseand pharmaceutically acceptable salts thereof. Pharmaceuticallyacceptable salts are salts that retain the desired biological activityof the parent compound and do not impart undesired toxicologicaleffects. Examples of such salts are (a) acid addition salts formed withinorganic acids, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid and the like; (b) saltsformed with organic acids such as, for example, acetic acid, oxalicacid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconicacid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid,palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonicacid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate,salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acidand the like; and (c) salts formed from elemental anions for example,chlorine, bromine, and iodine.

It is to be noted that all enantiomers, diastereomers, and racemicmixtures of compounds within the scope of formulas (I), (II) and (III)are embraced by the present invention and are included within anyreference to Formulas (I), (II) or (III) or compounds thereof.Additionally, all mixtures of such enantiomers and diastereomers arewithin the scope of the present invention and are included within anyreference to Formulas (I), (II) or (III) or compounds thereof.

In the compounds represented by these formulas, examples of halogeninclude fluorine, chlorine, bromine, and iodine. Chlorine and bromineare the preferred halogens. Chlorine is particularly preferred. Thisdescription is applicable to the term “halogen” as used throughout thepresent disclosure.

As used herein, the term “lower alkyl” means an alkyl group having lessthan 8 carbon atoms. This range includes all specific values of carbonatoms and subranges there between, such as 1, 2, 3, 4, 5, 6, and 7carbon atoms. The term “alkyl” embraces all types of such groups, e.g.,linear, branched, and cyclic alkyl groups. This description isapplicable to the term “lower alkyl” as used throughout the presentdisclosure. Examples of suitable lower alkyl groups include methyl,ethyl, propyl, cyclopropyl, butyl, isobutyl, etc.

As to Formula I, Y may be hydrogen, hydroxyl, mercapto, lower alkoxy,lower alkyl-thio, halogen, lower alkyl, lower cycloalkyl, mononucleararyl, or —N(R²)₂. The alkyl moiety of the lower alkoxy groups is thesame as described above. Examples of mononuclear aryl include phenylgroups. The phenyl group may be unsubstituted or substituted asdescribed above. The preferred identity of Y is —N(R²)₂Particularlypreferred are such compounds where each R₂ is hydrogen.

R¹ may be hydrogen or lower alkyl. Hydrogen is preferred for R¹.

Each R² may be, independently, —R⁷, —(CH₂)_(m)—OR⁸, —(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—(CH₂)_(n)-Z_(g)-R⁷, —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂)_(n)—CO₂R⁷, or

Hydrogen and lower alkyl, particularly C₁-C₃ alkyl are preferred for R²Hydrogen is particularly preferred.

R³ and R⁴ may be, independently, hydrogen, a group represented byformula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-loweralkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower(alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-loweralkyl, provided that at least one of R³ and R⁴ is a group represented byformula (A).

Preferred compounds are those where one of R³ and R⁴ is hydrogen and theother is represented by formula (A).

In formula (A), the moiety —(C(R^(L))₂)_(o)-x-(C(R^(L))₂)_(p)— definesan alkylene group bonded to the aromatic ring. The variables o and p mayeach be an integer from 0 to 10, subject to the proviso that the sum ofo and p in the chain is from 1 to 10. Thus, o and p may each be 0, 1, 2,3, 4, 5, 6, 7, 8, 9, or 10. Preferably, the sum of o and p is from 2 to6. In a particularly preferred embodiment of Formula I, the sum of o andp is 4.

The linking group in the alkylene chain, x, may be, independently, O,NR¹⁰, C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or represents a single bond;therefore, when x represents a single bond, the alkylene chain bonded tothe ring is represented by the formula —(C(R^(L))₂)_(o+p)—, in which thesum o+p is from 1 to 10.

Each R^(L) in Formula I may be, independently, —R⁷, —(CH₂)_(n)—OR⁸,—O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —O—(CH₂)m(CHOR⁸)(CHOR⁸)_(n)CH₂OR⁸,—(CH₂CH₂O)_(m)—R⁸, —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(m)—CO₂R⁷,—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

The preferred R^(L) groups for Formula I include —H, —OH, —N(R⁷)₂,especially where each R⁷ is hydrogen.

In the alkylene chain in formula (A), it is preferred that when oneR^(L) group bonded to a carbon atoms is other than hydrogen, then theother R^(L) bonded to that carbon atom is hydrogen, i.e., the formula—CHR^(L)—. It is also preferred that at most two R^(L) groups in analkylene chain are other than hydrogen, where in the other R^(L) groupsin the chain are hydrogens. Even more preferably, only one R^(L) groupin an alkylene chain is other than hydrogen, where in the other R^(L)groups in the chain are hydrogens. In these embodiments, it ispreferable that x represents a single bond.

In another particular embodiment of Formula I, all of the R^(L) groupsin the alkylene chain are hydrogen. In these embodiments, the alkylenechain is represented by the formula—(CH₂)_(o)—x—(CH₂)_(p)—.

In Formula I, each R⁵ is, independently, Link —(CH₂)_(n)—CAP, Link—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link —(CH₂CH₂O)_(m)—CH₂—CAP, Link—(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link —(CH₂)_(n)-(Z)_(g)-CAP, Link—(CH₂)_(n)(Z)_(g)-(CH₂)_(m)—CAP, Link—(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link NH—C(═O)—NH—(CH₂)_(m)—CAP, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰R¹⁰, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link—(CH₂)_(m)—C(═O)NR¹²R¹², Link —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP,Link -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP;

-   -   wherein Link is, independently, —O—, (CH₂)_(n)—, —O(CH₂)_(m)—,        —NR¹³—C(═O)—NR¹³, —NR¹³—C(═O)—(CH₂)_(m)—, —C(═O)NR¹³—(CH₂)_(m),        —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—, SO₂NR⁷—, SO₂NR¹⁰—,        -Het-;    -   wherein each CAP is, independently, thiazolidinedione,        oxazolidinedione, heteroaryl-C(═O)NR¹³R¹³, heteroaryl-CAP, —CN,        —O—C(═S)NR¹³R¹³, -Z_(g)R¹³, —CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³),        —C(═O)OAr, —C(═O)NR¹³Ar, imidazoline, tetrazole, tetrazole        amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³, cyclic sugars        and oligosaccharides, including cyclic amino sugars and        oligosaccharides,    -   wherein Ar is, independently, phenyl; Substituted phenyl,        wherein said substituent is 1-3 groups selected, independently,        from OH, OCH₃, NR¹³R¹³, Cl, F, CH₃; heteroaryl, e.g., pyridine,        pyrazine, tinazine, furyl, furfuryl-, thienyl, tetrazole,        thiazolidinedione and imidazoyl (        ) and other heteroaromatic ring systems as defined below;    -   wherein heteroaryl is selected from one of the following        heteroaromatic systems:    -   Pyrrole, Furan, Thiophene, Pyridine, Quinoline, Indole, Adenine,        Pyrazole, Imidazole, Thiazole, Isoxazole, Indole, Benzimidazole,        Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,        Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine,        Cinnoline, Phthalazine, Quinazoline, Quinoxaline and Pterdine;    -   each R⁶ is, independently, —R⁷, —OR⁷, —OR¹¹, —N(R⁷)₂,        —(CH₂)_(m)—OR⁸, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰,        —O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,        —O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,        —O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,        —O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,        —O—(CH₂)_(m)-(Z)_(g)-R⁷,        —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,        —(CH₂)_(n)—CO₂R⁷, —O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O        -glucose,    -   where when two R⁶ are —OR¹¹ and are located adjacent to each        other on a phenyl ring, the alkyl moieties of the two R⁶ may be        bonded together to form a methylenedioxy group;    -   with the proviso that when at least two —CH₂OR⁸ are located        adjacent to each other, the R⁸ groups may be joined to form a        cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane.

In addition, one of more of the R⁶ groups can be one of the R⁵ groupswhich fall within the broad definition of R⁶ set forth above.

When two R⁶ are —OR¹¹ and are located adjacent to each other on a phenylring, the alkyl moieties of the two R⁶ groups may be bonded together toform a methylenedioxy group, i.e., a group of the formula —O—CH₂—O—.

As discussed above, R⁶ may be hydrogen. Therefore, 1, 2, 3, or 4 R⁶groups may be other than hydrogen. Preferably at most 3 of the R⁶ groupsare other than hydrogen.

Each g is, independently, an integer from 1 to 6. Therefore, each g maybe 1, 2, 3, 4, 5, or 6.

Each m is an integer from 1 to 7. Therefore, each m may be 1, 2, 3, 4,5, 6, or 7.

Each n is an integer from 0 to 7. Therefore, each n may be 0, 1, 2, 3,4, 5, 6, or 7.

Each Q in formula (A) is C—R⁵, C—R⁶, or a nitrogen atom, where at mostthree Q in a ring are nitrogen atoms. Thus, there may be 1, 2, or 3nitrogen atoms in a ring. Preferably, at most two Q are nitrogen atoms.More preferably, at most one Q is a nitrogen atom. In one particularembodiment, the nitrogen atom is at the 3-position of the ring. Inanother embodiment of the invention, each Q is either C—R⁵ or C—R⁶,i.e., there are no nitrogen atoms in the ring.

More specific examples of suitable groups represented by formula (A) areshown in formulas (B)-(E) below:

-   -   where o, x, p, R⁵, and R⁶, are as defined above;    -   where n is an integer from 1 to 10 and R⁵ is as defined above;    -   where n is an integer from 1 from 10 and R⁵ is as defined above;    -   where o, x, p, and R⁵ are as defined above.

In a preferred embodiment of Formula I, Y is —NH₂.

In another preferred embodiment of Formula I, R² is hydrogen.

In another preferred embodiment of Formula I, R¹ is hydrogen.

In another preferred embodiment of Formula I, X is chlorine.

In another preferred embodiment of Formula I, R³ is hydrogen.

In another preferred embodiment of Formula I, R^(L) is hydrogen.

In another preferred embodiment of Formula I, o is 4.

In another preferred embodiment of Formula I, p is 0.

In another preferred embodiment of Formula I, the sum of o and p is 4.

In another preferred embodiment of Formula I, x represents a singlebond.

In another preferred embodiment of Formula I, R⁶ is hydrogen.

In another preferred embodiment of Formula I, at most one Q is anitrogen atom.

In another preferred embodiment of Formula I, no Q is a nitrogen atom.

In a preferred embodiment of Formula I:

-   -   X is halogen;    -   Y is —NR⁷)₂;    -   R¹ is hydrogen or C₁-C₃ alkyl;    -   R² is —R⁷, —R⁷, CH₂OR⁷, or —CO₂R⁷;    -   R³ is a group represented by formula (A); and R⁴ is hydrogen, a        group represented by formula (A), or lower alkyl.

In another preferred embodiment of Formula I:

-   -   X is chloro or bromo;    -   Y is —N(R⁷)₂;    -   R² is hydrogen or C₁-C₃ alkyl;    -   at most three R⁶ are other than hydrogen as described above;    -   at most three R^(L) are other than hydrogen as described above;        and at most 2 Q are nitrogen atoms.

In another preferred embodiment of Formula I:

-   -   Y is —NH₂.

In another preferred embodiment of Formula I:

-   -   R⁴ is hydrogen;    -   at most one R^(L) is other than hydrogen as described above;    -   at most two R⁶ are other than hydrogen as described above; and        at most 1 Q is a nitrogen atom.

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

In another preferred embodiment, the compound of formula (I) isrepresented by the formula:

As to Formula II, in a preferred embodiment, each —(CH₂)_(n)-(Z)_(g)-R⁷falls within the scope of the structures described above and is,independently,

-   -   —(CH₂)_(n)—(C═N)—NH₂,    -   —(CH₂)_(n)—NH—C(═NH)NH₂,    -   —(CH₂)_(n)—CONHCH₂(CHOH)_(n)—CH₂OH,    -   —NH—C(═O)—CH₂—(CHOH)_(n)—CH₂OH.

In another a preferred embodiment of Formula II, each—O—(CH₂)_(m)-(Z)_(g)-R⁷ falls within the scope of the structuresdescribed above and is, independently,

-   -   —O—(CH₂)_(M)—NH—C(═NH)—N(R⁷)₂,    -   —O—(CH₂)_(m)CHNH₂—CO₂NR⁷R¹⁰

In another preferred embodiment of Formula II, each R^(5′) falls withinthe scope of the structures described above and is, independently,

-   -   —O—CH₂CHOHCH₂, O-glucuronide,    -   —OCH₂CHOHCH₃,    -   —OCH₂CH₂NH₂,    -   —OCH₂CH₂NHCO(CH₃)₃,    -   —CH₂CH₂OH,    -   —OCH₂CH₂OH,    -   —O—(CH₂)_(m)-Boc,    -   —(CH₂)_(m)—Boc,    -   —OCH₂CH₂OH,    -   —OCH₂CO₂H,    -   —O—(CH₂)_(m)—NH—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—NH—C(═NH)—N(R⁷)₂,    -   —NHCH₂(CHOH)₂—CH₂OH,    -   —OCH₂CO₂Et,    -   —NHSO₂CH₃,    -   —(CH₂)_(m)NH—C(═O)—OR⁷,    -   —O—(CH₂)_(m)—NH—C(═O)—OR⁷,    -   —(CH₂)_(n)—NH—C(═O)—R¹¹,    -   —O—(CH₂)_(m)—NH—C(═O)—R¹¹,    -   —O—CH₂C(═O)NH₂,    -   —CH₂NH₂,    -   —NHCO₂Et,    -   —OCH₂CH₂CH₂CH₂OH,    -   —CH₂NHSO₂CH₃,    -   —OCH₂CH₂CHOHCH₂OH,    -   —OCH₂CH₂NHCO₂Et,    -   —NH—C(═NH₂)—NH₂,    -   —OCH₂-(α-CHOH)₂—CH₂OH    -   —OCH₂CHOHCH₂NH₂,    -   —(CH₂)_(m)—CHOH—CH₂—NHBOC,    -   —O—(CH₂)_(m)—CHOH—CH₂—NHBoc,    -   —(CH₂)_(m)—NHC(O)OR⁷,    -   —O—(CH₂)_(m)—NHC(O)OR⁷,    -   —OCH₂CH₂CH₂NH₂,    -   —OCH₂CH₂NHCH₂(CHOH)₂CH₂OH,    -   —OCH₂CH₂NH(CH₂[(CHOH)₂CH₂OH)]₂,    -   —(CH₂)₄—NHBoc,    -   —(CH₂)₄—NH₂,    -   —(CH₂)₄—OH,    -   —OCH₂CH₂NHSO₂CH₃,    -   —O—(CH₂)_(m)—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—C(═NH)—N(R⁷)₂,    -   —(CH₂)₃—NH Boc,    -   —(CH₂)₃NH₂,    -   —O—(CH₂)_(m)—NH—NH—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—NH—NH—C(═NH)—N(R₇)₂, or    -   —O—CH₂—CHOH—CH₂—NH—C(═NH)—N(R⁷)₂;

Preferred examples of R^(5′) in the embodiments of Formula II describedabove include:

-   -   —N(SO₂CH₃)₂,    -   —CH₂—CHNHBocCO₂CH₃ (α),    -   —O—CH₂—CHNH₂CO₂H (α),    -   —O—CH₂—CHNH₂CO₂CH₃ (α),    -   —O—(CH₂)₂—N⁺(CH₃)₃,    -   —C(═O)NH—(CH₂)₂—NH₂, and    -   —C(═O)NH—(CH₂)₂—NH—C(═NH)—NH₂.

Preferred examples of R^(5′) also include:

-   -   —N(SO₂CH₃)₂,    -   —CH₂—CHNHBocCO₂CH₃ (α),    -   —O—CH₂—CHNH₂CO₂H (α),    -   —O—CH₂—CHNH₂CO₂CH₃ (α),    -   —O—(CH₂)₂—N⁺(CH₃)₃,    -   —C(═O)NH—(CH₂)₂—NH₂,    -   —C(═O)NH—(CH₂)₂—NH—C(═NH)—NH₂, and

In Formula II, the preferred identity of Y is —N(R²)₂. Particularlypreferred are such compounds where each R² is hydrogen.

R¹ in Formula II may be hydrogen or lower alkyl. Hydrogen is preferredfor R¹.

R³′ and R⁴′ may be, independently, hydrogen, a group represented byformula (A′), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-loweralkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower(alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-loweralkyl, provided that at least one of R^(3′) and R^(4′) is a grouprepresented by formula (A′).

Preferred compounds of Formula II are those where one of R^(3′) and R⁴⁰is hydrogen and the other is represented by formula (A′).

In formula (A′), the moiety —(C(R^(L))₂)_(o)-x-(C(R^(L))₂)_(p)— definesan alkylene group. The variables o and p may each be an integer from 0to 10, subject to the proviso that the sum of o and p in the chain isfrom 1 to 10. Thus, o and p may each be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or10. Preferably, the sum of o and p is from 2 to 6. In a particularlypreferred embodiment, the sum of o and p is 4.

The linking group in the alkylene chain of Formula II, x, may be,independently, O, NR¹⁰, C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or representsa single bond; therefore, when x represents a single bond, the alkylenechain bonded to the ring is represented by the formula—(C(R^(L))₂)_(o+p)—, in which the sum o+p is from 1 to 10.

The preferred R^(L) groups in Formula II include —H, —OH, —N(R⁷)₂,especially where each R⁷ is hydrogen.

In the alkylene chain in formula (A′), it is preferred that when oneR^(L) group bonded to a carbon atoms is other than hydrogen, then theother R^(L) bonded to that carbon atom is hydrogen, i.e., the formula—CHR^(L)—. It is also preferred that at most two R^(L) groups in analkylene chain are other than hydrogen, where in the other R^(L) groupsin the chain are hydrogens. Even more preferably, only one R^(L) groupin an alkylene chain is other than hydrogen, where in the other R^(L)groups in the chain are hydrogens. In these embodiments, it ispreferable that x represents a single bond.

In another particular embodiment of Formula II, all of the R^(L) groupsin the alkylene chain are hydrogen. In these embodiments, the alkylenechain is represented by the formula—(CH₂)_(o)-x-(CH₂)_(p)—.

As discussed above, R may be hydrogen. Therefore, 1 or 2 R^(6′) groupsmay be other than hydrogen. Preferably at most 3 of the R^(6′) groupsare other than hydrogen.

Each g is, independently, an integer from 1 to 6. Therefore, each g maybe 1, 2,3,4, 5,or 6.

Each m is an integer from 1 to 7. Therefore, each m may be 1, 2, 3, 4,5, 6, or 7.

Each n is an integer from 0 to 7. Therefore, each n maybe 0, 1, 2, 3, 4,5, 6, or 7.

In a preferred embodiment of Formula II, Y is —NH₂.

In another preferred embodiment of Formula II, R² is hydrogen.

In another preferred embodiment of Formula II, R¹ is hydrogen.

In another preferred embodiment of Formula II, X is chlorine.

In another preferred embodiment of Formula II, R^(3′) is hydrogen.

In another preferred embodiment of Formula II, R^(L) is hydrogen.

In another preferred embodiment of Formula II, o is 4.

In another preferred embodiment of Formula II, p is 0.

In another preferred embodiment of Formula II, the sum of o and p is 4.

In another preferred embodiment of Formula II, x represents a singlebond.

In another preferred embodiment of Formula II, R^(6′) is hydrogen.

In a preferred embodiment of Formula II:

-   -   X is halogen;    -   Y is —N(R⁷)₂;    -   R¹ is hydrogen or C₁-C₃ alkyl;    -   R² is —R⁷, —OR⁷, CH₂O⁷, or —CO₂R⁷;    -   R^(3′) is a group represented by formula (A′); and    -   R^(4′) is hydrogen, a group represented by formula (A′), or        lower alkyl.

In another preferred embodiment of Formula II:

-   -   X is chloro or bromo;    -   Y is —N(R⁷)₂;    -   R² is hydrogen or C₁-C₃ alkyl;    -   at most three R^(6′) are other than hydrogen as described above;    -   at most three R^(L) are other than hydrogen as described above.

In another preferred embodiment of Formula II:

-   -   Y is —NH₂.

In another preferred embodiment of Formula II:

-   -   R⁴′ is hydrogen;    -   at most one R^(L) is other than hydrogen as described above;    -   at most two R⁶ are other than hydrogen as described above.

In another preferred embodiment, formula (II) is represented by theformula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

In another preferred embodiment, the compound of formula (II) isrepresented by the formula:

As to Formula III, in a preferred embodiment, each —(CH₂)_(n)-(Z)_(g)-R⁷falls within the scope of the structures described above and is,independently,

-   -   —(CH₂)_(n)—(C═N)—NH₂,    -   —(CH₂)_(m)—NH—C(═NH)NH₂,    -   —(CH₂)_(n)—CONHCH₂(CHOH)₂—CH₂OH,    -   —NH—C(═O)—CH₂—(CHOH)_(n)CH₂OH.

In another a preferred embodiment of Formula III, each—O—(CH₂)_(m)-(Z)_(g)R^(7,) falls within the scope of the structuresdescribed above and is, independently,

-   -   —O—(CH₂)_(M)—NH—C(═NH)—N(R⁷)₂,    -   —O—(CH₂)_(m)—CHNH₂—CO₂NR⁷R¹⁰

In another preferred embodiment of Formula III, each R^(5′) falls withinthe scope of the structures described above and is, independently,

-   -   —O—CH₂CHOHCH₂O-glucuronide,    -   —OCH₂CHOHCH₃,    -   —OCH₂CH₂NH₂,    -   —OCH₂CH₂NHCO(CH₃)₃,    -   —CH₂CH₂OH,    -   —OCH₂CH₂OH,    -   —O—(CH₂)_(m)-Boc,    -   —(CH₂)_(m)-Boc,    -   —OCH₂CH₂OH,    -   —OCH₂CO₂H,    -   —O—(CH₂)_(m)—NH—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—NH—C(═NH)—N(R⁷)₂,    -   —NHCH₂(CHOH)₂—CH₂OH,    -   —OCH₂CO₂Et,    -   —NHSO₂CH₃,    -   —(CH₂)_(m)—NH—C(═O)—OR⁷,    -   —O—(CH₂)_(m)—NH—C(═O)—OR⁷,    -   —(CH₂)_(n)—NH—C(═O)—R¹¹,    -   —O—(CH₂)_(m)—NH—C(═O)—R¹¹,    -   —O—CH₂C(═O)NH₂,    -   —CH₂NH₂,    -   —NHCO₂Et,    -   —OCH₂CH₂CH₂CH₂OH,    -   —CH₂NHSO₂CH₃,    -   —OCH₂CH₂CHOHCH₂OH,    -   —OCH₂CH₂NHCO₂Et,    -   —NH—C(═NH₂)—NH₂,    -   —OCH₂—(α(—CHOH)₂—CH₂OH    -   —OCH₂CHOHCH₂NH₂,    -   —(CH₂)_(m)—CHOH—CH₂—NHBoc,    -   —O—(CH₂)_(m)—CHOH—CH₂—NHBoc,    -   —(CH₂)_(m)—NHC(O)OR⁷,    -   —O—(CH₂)_(m)—NHC(O)OR⁷,    -   —OCH₂CH₂CH₂NH₂,    -   —OCH₂CH₂NHCH₂(CHOH)₂CH₂OH,    -   —OCH₂CH₂NH(CH₂[(CHOH)₂CH₂OH)]₂,    -   —(CH₂)₄—NHBoc,    -   —(CH₂)₄—NH₂,    -   —(CH₂)₄—OH,    -   —OCH₂CH₂NHSO₂CH₃,    -   —O—(CH₂)_(m)—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—C(═NH)—N(R⁷)₂,    -   —(CH₂)₃—NH Boc,    -   —(CH₂)₃NH₂,    -   —O—(CH₂)_(m)—NH—NH—C(═NH)—N(R⁷)₂,    -   —(CH₂)_(n)—NH—NH—C(═NH)—N(R⁷)₂, or    -   —O—CH₂—CHOH—CH₂—NH—C(═NH)—N(R⁷)₂;

Preferred examples of R^(5′) in the embodiments described above include:

-   -   —N(SO₂CH₃)₂,    -   —CH₂—CHNHBocCO₂CH₃ (α),    -   —O—CH₂—CHNH₂CO₂H (α),    -   —O—CH₂—CHNH₂CO₂CH₃ (α),    -   —O—(CH₂)₂—N⁺(CH₃)₃,    -   —C(═O)NH—(CH₂)₂—NH₂, and    -   —C(═O)NH—(CH₂)₂—NH—C(═NH)—NH₂.

Preferred examples of R^(5′) also include:

-   -   —N(SO₂CH₃)₂,    -   —CH₂—CHNHBocCO₂CH₃ (α),    -   —O—CH₂—CHNH₂CO₂H (α),    -   —O—CH₂—CHNH₂CO₂CH₃ (α),    -   —O—(CH₂)₂—N⁺(CH₃)₃,    -   —C(═O)NH—(CH₂)₂—NH₂,    -   —C(═O)NH—(CH₂)₂—NH—C(═NH)—NH₂, and

Substituents for the phenyl group where applicable in Formula IIIinclude halogens. Particularly preferred halogen substituents arechlorine and bromine.

Y in Formula III may be hydrogen, hydroxyl, mercapto, lower alkoxy,lower alkyl-thio, halogen, lower alkyl, lower cycloalkyl, mononucleararyl, or —N(R²)₂. The alkyl moiety of the lower alkoxy groups is thesame as described above. Examples of mononuclear aryl include phenylgroups. The phenyl group may be unsubstituted or substituted asdescribed above. The preferred identity of Y is —N(R²)₂. Particularlypreferred are such compounds where each R² is hydrogen.

R¹ may be hydrogen or lower alkyl in Formula III. Hydrogen is preferredfor R¹.

Hydrogen and lower alkyl, particularly C₁-C₃ alkyl are preferred for R²in Formula III. Hydrogen is particularly preferred.

Preferred compounds of Formula III are those where one of R^(3″) andR^(4″) is hydrogen and the other is represented by formula (A″).

In formula (A″), the moiety —(C(R^(L))₂)_(o)-x-(C(R^(L))₂)_(p)— definesan alkylene group bonded to the cyclic ring. The variables o and p mayeach be an integer from 0 to 10, subject to the proviso that the sum ofo and p in the chain is from 1 to 10. Thus, o and p may each be 0, 1, 2,3, 4, 5, 6, 7, 8, 9, or 10. Preferably, the sum of o and p is from 2 to6. In a particularly preferred embodiment, the sum of o and p is 4.

The linking group in the alkylene chain, x, may be, independently, O,NR¹⁰, C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or represents a single bond;therefore, when x represents a single bond, the alkylene chain bonded tothe ring is represented by the formula —(C(R^(L))₂)_(o+p)—, in which thesum o+p is from 1 to 10.

The preferred R^(L) groups in Formula III include —H, —OH, —N(R⁷)₂,especially where each R⁷ is hydrogen.

In the alkylene chain in formula (A″), it is preferred that when oneR^(L) group bonded to a carbon atoms is other than hydrogen, then theother R^(L) bonded to that carbon atom is hydrogen, i.e., the formula—CHR^(L)—. It is also preferred that at most two R^(L) groups in analkylene chain are other than hydrogen, where in the other R^(L) groupsin the chain are hydrogens. Even more preferably, only one R^(L) groupin an alkylene chain is other than hydrogen, where in the other R^(L)groups in the chain are hydrogens. In these embodiments, it ispreferable that x represents a single bond.

In another particular embodiment of the invention, all of the R^(L)groups in the alkylene chain are hydrogen. In these embodiments, thealkylene chain is represented by the formula—(CH₂)_(o)-x-(CH₂)_(p)—.

Each g is, independently, an integer from 1 to 6. Therefore, each g maybe 1, 2, 3, 4, 5, or 6.

Each m is an integer from 1 to 7. Therefore, each m may be 1, 2, 3, 4,5, 6, or 7.

Each n is an integer from 0 to 7. Therefore, each n maybe 0, 1, 2, 3, 4,5, 6, or 7.

Each Q′ is, independently, —CHR^(5′), —CHR^(6′), —NR⁷, —NR¹⁰, —S—, —SO—,or —SO₂—; wherein at most three Q′ in a ring contain a heteroatom and atleast one Q′ must be —CHR^(5′). Thus, there may be 1, 2, or 3 nitrogenatoms in a ring. Preferably, at most two Q′ are nitrogen atoms.

In a preferred embodiment of Formula III, Y is —NH₂.

In another preferred embodiment Formula III, R² is hydrogen.

In another preferred embodiment Formula III, R¹ is hydrogen.

In another preferred embodiment Formula III, X is chlorine.

In another preferred embodiment Formula III, R^(3′) is hydrogen.

In another preferred embodiment Formula III, R^(L) is hydrogen.

In another preferred embodiment Formula III, o is 4.

In another preferred embodiment Formula III, p is 0.

In another preferred embodiment Formula III, the sum of o and p is 4.

In another preferred embodiment Formula III, x represents a single bond.

In another preferred embodiment Formula III, R^(6′) is hydrogen.

In another preferred embodiment Formula III, at most 2 Q′ are nitrogenatoms.

In another preferred embodiment Formula III, at most one Q′ is anitrogen atom.

In another preferred embodiment Formula III, no Q′ is a nitrogen atom.

In a preferred embodiment of Formula III:

-   -   X is halogen;    -   Y is —N(R⁷)₂;    -   R¹ is hydrogen or C₁-C₃ alkyl;    -   R² is —R⁷, —OR⁷, CH₂O⁷, or —CO₂R⁷;    -   R^(3″) is a group represented by formula (A″); and    -   R^(4″) is hydrogen, a group represented by formula (A″), or        lower alkyl.

In another preferred embodiment of Formula III:

-   -   X is chloro or bromo;    -   Y is —N(R⁷)₂;    -   R² is hydrogen or C₁-C₃ alkyl;    -   at most three R^(6′) are other than hydrogen as described above;    -   at most three R^(L) are other than hydrogen as described above;        and    -   at most 2 Q′ are nitrogen atoms.

In another preferred embodiment of Formula III:

-   -   Y is —NH₂;

In another preferred embodiment of Formula III:

-   -   R⁴ is hydrogen;    -   at most one R^(L) is other than hydrogen as described above;    -   at most two R^(6′) are other than hydrogen as described above;        and    -   at most 1 Q′ is a nitrogen atom.

In another preferred embodiment of Formula III, the compound isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

In another preferred embodiment, the compound of formula (III) isrepresented by the formula:

The active compounds disclosed herein may be administered to the lungsof a patient by any suitable means, but are preferably administered byadministering an aerosol suspension of respirable particles comprised ofthe active compound, which the subject inhales. The compounds may beinhaled through the mouth or the nose. The active compound can beaerosolized in a variety of forms, such as, but not limited to, drypowder inhalants, metered dose inhalants or liquid/liquid suspensions.The quantity of sodium channel blocker included may be an amountsufficient to achieve the desired effect and as described in theattached applications.

Solid or liquid particulate sodium channel blocker prepared forpracticing the present invention should include particles of respirablesize: that is, particles of a size sufficiently small to pass throughthe mouth and larynx upon inhalation and into the bronchi and alveoli ofthe lungs. In general, particles ranging from about 1 to 5 microns insize (more particularly, less than about 4.7 microns in size) arerespirable. Particles of non-respirable size which are included in theaerosol tend to be deposited in the throat and swallowed, and thequantity of non-respirable particles in the aerosol is preferablyminimized. For nasal administration, a particle size in the range of10-500 μm is preferred to ensure retention in the nasal cavity. Nasaladministration may be useful where the pathogen typically enters throughthe nose. However, it is preferred to administer at least a portion ofthe sodium channel blocker in a dosage form which reaches the lungs toensure effective prophylactic treatment in cases where the pathogen isexpected to reach the lungs.

The dosage of active compound will vary depending on the prophylacticeffect desired and the state of the subject, but generally may be anamount sufficient to achieve dissolved concentrations of active compoundon the airway surfaces of the subject as described in the attachedapplications. Depending upon the solubility of the particularformulation of active compound administered, the daily dose may bedivided among one or several unit dose administrations. The dosage maybe provided as a prepackaged unit by any suitable means (e.g.,encapsulating in a gelatin capsule).

Pharmaceutical formulations suitable for airway administration includeformulations of solutions, emulsions, suspensions and extracts. Seegenerally, J. Naim, Solutions, Emulsions, Suspensions and Extracts, inRemington: The Science and practice of Pharmacy, chap. 86 (19^(th) ed.1995). Pharmaceutical formulations suitable for nasal administration maybe prepared as described in U.S. Pat. No. 4,389,393 to Schor; U.S. Pat.No. 5,707,644 to Illum, U.S. Pat. No. 4,294,829 to Suzuki, and 4,835,142to Suzuki.

In the manufacture of a formulation according to the invention, activeagents or the physiologically acceptable salts or free bases thereof aretypically admixed with, inter alia, an acceptable carrier. The carriermust, of course, be acceptable in the sense of being compatible with anyother ingredients in the formulation and must not be deleterious to thepatient. The carrier may be a solid or a liquid, or both, and ispreferably formulated with the compound as a unit-dose formulation, forexample, a capsule, which may contain from 0.5% to 99% by weight of theactive compound. One or more active compounds may be incorporated in theformulations of the invention, which formulations may be prepared by anyof the well-known techniques of pharmacy consisting essentially ofadmixing the components.

Aerosols or mists of liquid particles comprising the active compound maybe produced by any suitable means, such as, for nasal administration, bya simple nasal spray with the active compound in an aqueouspharmaceutically acceptable carrier such as sterile saline solution orsterile water. Other means include producing aerosols with apressure-driven aerosol nebulizer or an ultrasonic nebulizer. See, e.g.,U.S. Pat. No. 4,501,729. Nebulizers are commercially available deviceswhich transform solutions or suspensions of the active ingredient into atherapeutic aerosol mist either by means of acceleration of compressedgas, typically air or oxygen, through a narrow venturi orifice or bymeans of ultrasonic agitation. Suitable formulations for use innebulizers may consist of the active ingredient in a liquid carrier. Thecarrier is typically water (and most preferably sterile, pyrogen-freewater) or a dilute aqueous alcoholic solution, preferably made isotonicwith body fluids by the addition of, for example, sodium chloride.

Aerosols or mists of solid particles comprising the active compound maylikewise be produced with any solid particulate medicament aerosolgenerator. Aerosol generators for administering solid particulatemedicaments to a subject produce particles which are respirable, asexplained above, and generate a volume of aerosol containing apredetermined metered dose of a medicament at a rate suitable for humanadministration. Such aerosol generators are known in the art. By way ofexample, see U.S. Pat. No. 5,725,842.

One illustrative type of solid particulate aerosol generator is aninsufflator. Suitable formulations for administration by insufflationinclude finely comminuted powders which may be delivered by means of aninsufflator or taken into the nasal cavity in the manner of a snuff. Inthe insufflator, the powder (e.g., a metered dose thereof effective tocarry out the treatments described herein) is contained in capsules orcartridges, typically made of gelatin or plastic, which are eitherpierced or opened in situ and the powder delivered by air drawn throughthe device upon inhalation or by means of a manually-operated pump. Thepowder employed in the insufflator consists either solely of the activeingredient or of a powder blend comprising the active ingredient, asuitable powder diluent, such as lactose, and an optional surfactant.

A second type of illustrative aerosol generator comprises a metered doseinhaler. Metered dose inhalers are pressurized aerosol dispensers,typically containing a suspension or solution formulation of the activeingredient in a liquefied propellant. During use these devices dischargethe formulation through a valve adapted to deliver a metered volume,typically from 10 to 150 μl to produce a fine particle spray containingthe active ingredient. Any propellant may be used in carrying out thepresent invention, including both chlorofluorocarbon-containingpropellants and non-chlorofluorocarbon-containing propellants. Suitablepropellants include certain chlorofluorocarbon compounds, for example,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane and mixtures thereof.

The formulation may additionally contain one or more co-solvents, forexample, ethanol, surfactants, such as oleic acid or sorbitan trioleate,antioxidants, preservatives such as methyl hydroxybenzoate, volatileoils, buffering agents and suitable flavoring agents.

Compositions containing respirable dry particles of sodium channelblockers as described in the attached applications may be prepared asdetailed in those applications. The active compound may be formulatedalone (i.e., the solid particulate composition may consist essentiallyof the active compound) or in combination with a dispersant, diluent orcarrier, such as sugars (i.e., lactose, sucrose, trehalose, mannitol) orother acceptable excipients for lung or airway delivery, which may beblended with the active compound in any suitable ratio (e.g., a 1 to 1ratio by weight). The dry powder solid particulate compound may beobtained by methods known in the art, such as spray-drying, milling,freeze-drying, and the like.

The aerosol or mist, whether formed from solid or liquid particles, maybe produced by the aerosol generator at a rate of from about 10 to about150 liters per minute, more preferably from about 30 to about 150 litersper minute, and most preferably about 60 liters per minute. Aerosolscontaining greater amounts of medicament may be administered morerapidly.

Other medicaments may be administered with the active compoundsdisclosed if such medicament is compatible with the active compound andother ingredients in the formulation and can be administered asdescribed herein.

The pathogens which may be protected against by the prophylactic postexposure, rescue and therapeutic treatment methods of the inventioninclude any pathogens which may enter the body through the mouth, noseor nasal airways, thus proceeding into the lungs. Typically, thepathogens will be airborne pathogens, either naturally occurring or byaerosolization. The pathogens may be naturally occurring or may havebeen introduced into the environment intentionally after aerosolizationor other method of introducing the pathogens into the environment. Manypathogens which are not naturally transmitted in the air have been ormay be aerosolized for use in bioterrorism.

The pathogens for which the treatment of the invention may be usefulincludes, but is not limited to, category A, B and C priority pathogensas set forth by the NIAID. These categories correspond generally to thelists compiled by the Centers for Disease Control and Prevention (CDC).As set up by the CDC, Category A agents are those that can be easilydisseminated or transmitted person-to-person, cause high mortality, withpotential for major public health impact. Category B agents are next inpriority and include those that are moderately easy to disseminate andcause moderate morbidity and low mortality. Category C consists ofemerging pathogens that could be engineered for mass dissemination inthe future because of their availability, ease of production anddissemination and potential for high morbidity and mortality.

Category A: Bacillus anthracis (anthrax),

-   -   Clostridium botulinum (botulism),    -   Yersinia pestis (plague),    -   Variola major (smallpox) and other pox viruses,    -   Francisella tularensis (tularemia),    -   Viral hemorrhagic fevers    -   Arenaviruses,        -   LCM (lymphocytic choriomeningitis), Junin virus,    -   Machupo virus, Guanarite virus,        -   Lassa Fever,    -   Bunyaviruses,        -   Hantavirus,        -   Rift Valley Fever,    -   Flaviviruses,        -   Dengue,    -   Filoviruses,        -   Ebola        -   Marburg;

Category B: Burkholderia pseudomallei (melioidosis),

-   -   Coxiella burnetii (Q fever),    -   Brucella species (brucellosis),    -   Burkholderia mallei (glanders),    -   Ricin toxin from Ricinus communis,    -   Epsilon toxin of Clostridium perfringens,    -   Staphylococcal enterotoxin B,    -   Typhus fever (Rickettsia prowazekii),    -   Food and water-borne pathogens        -   bacteria:            -   Diarrheagenic Escherichia coli,            -   Pathogenic vibrios,            -   Shigella species,            -   Salmonella species,            -   Listeria monocytogenes,            -   campylobacter jejuni,            -   Yersinia enterocolitica;        -   Viruses            -   Caliciviruses,            -   Hepatitis A;        -   Protozoa            -   Cryptosporidium parvum,            -   Cyclospora cayatenensis,            -   Giardia lamblia,            -   Entamoeba histolytica,            -   Toxoplasma,            -   Microsporidia, and        -   Additional viral encephalitides            -   West Nile virus,            -   LaCrosse,            -   California encephalitis,            -   Venezuelan equine encephalitis,            -   Eastern equine encephalitis,            -   Western equine encephalitis,            -   Japanese encephalitis virus and            -   Kyasanur forest virus, and

Category C: emerging infectious disease threats such as Nipah virus andadditional hantaviruses, tickborne hemorrhagic fever viruses such asCrimean Congo hemorrhagic fever virus, tickborne encephalitis viruses,yellow fever, multi-drug resistant tuberculosis, influenza, otherrickettsias and rabies.

Additional pathogens which may be protected against or the infectionrisk therefrom reduced include influenza viruses, rhinoviruses,adenoviruses and respiratory syncytial viruses, and the like. A furtherpathogen which may be protected against is the coronavirus which isbelieved to cause severe acute respiratory syndrome (SARS).

A number of the above-listed pathogens are known to be particularlyharmful when introduced into the body through the air. For example,Bacillus anthracis, the agent which causes anthrax, has three majorclinical forms, cutaneous, inhalational, and gastrointestinal. All threeforms may lead to death but early antibiotic treatment of cutaneous andgastrointestinal anthrax usually cures those forms of anthrax.Inhalational anthrax, on the other hand, is a potentially fatal diseaseeven with antibiotic treatment. Initial symptoms may resemble a commoncold. After several days, the symptoms may progress to severe breathingproblems and shock. For naturally occurring or accidental infections,even with appropriate antibiotics and all other available supportivecare, the historical fatality rate is believed to be about 75 percent,according to the NIAID. Inhalational anthrax develops after spores aredeposited in alveolar spaces and subsequently ingested by pulmonaryalveolar macrophages. Surviving spores are then transported to themediastinal lymph nodes, where they may germinate up to 60 days orlonger. After germination, replicating bacteria release toxins thatresult in disease. This process is interrupted by administration of aprophylactically effective amount of a sodium channel blocker, as thespores may be wholly or partially eliminated from the body by removal oflung mucous secretions hydrated through the action of the sodium channelblocker.

Another pathogen of primary concern as one of the most dangerouspotential biological weapons because it is easily transmitted fromperson to person, no effective therapy exists and few people carry fullimmunity to the virus, is the small pox virus, Variola major. Smallpoxspreads directly from person to person, primarily by aerosolized salivadroplets expelled from an infected person. Initial symptoms include highfever, fatigue, headache and backache followed in two or three days by acharacteristic rash.

An embodiment of the present invention provides a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to smallpox virus or other pox virus comprising theadministration of a prophylactically effective amount of a sodiumchannel blocker. The administration of an effective amount of a sodiumchannel blocker will function to allow the Variola major virus or otherpox virus present in the aerosolized saliva droplets to which theindividual was exposed to be wholly or partially removed from the bodyby removal of hydrated lung mucous secretions hydrated through theaction of the sodium channel blocker.

The bacterium Yersinia pestis causes plague and is widely availablethroughout the world. NIAID has reported that infection by inhalation ofeven small numbers of virulent aerosolized Y. pestis bacilli can lead topneumonic plague, which has a mortality rate of almost 100% if leftuntreated. Pneumonic plague has initial symptoms of fever and coughwhich resemble other respiratory illnesses. Antibiotics are effectiveagainst plague but success with antibiotics depends on how quickly drugtherapy is started, the dose of inhaled bacteria and the level ofsupportive care for the patient; an effective vaccine is not widelyavailable.

An embodiment of the present invention provides a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to aerosolized Y. pestis bacilli comprising the administrationof a sodium channel blocker. The administration of an effective amountof a sodium channel blocker will function to allow the aerosolized Y.pestis bacilli to be wholly or partially removed from the body byremoval of hydrated lung mucous secretions hydrated through the actionof the sodium channel blocker.

Botulinum toxin is another substance believed to present a majorbioterrorism threat as it is easily released into the environment.Antibiotics are not effective against botulinum toxin and no approvedvaccine exists. Although the toxin may be transmitted through food, thebotulinum toxin is absorbed across mucosal surfaces and, thus,embodiments of the present invention provide a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to botulinum toxin comprising the administration of a sodiumchannel blocker.

The NIAID has identified the bacteria that causes tularemia as apotential bioterrorist agent because Francisella tularensis is capableof causing infection with as few as ten organisms and due to its abilityto be aerosolized. Natural infection occurs after inhalation of airborneparticles. Tularemia may be treated with antibiotics and an experimentalvaccine exists but knowledge of optimal therapeutic approaches fortularemia is limited because very few investigators are working on thisdisease. An embodiment of the present invention provides a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to aerosolized Francisella tularensis comprising theadministration of a sodium channel blocker. The administration of aneffective amount of a sodium channel blocker will function to allow theaerosolized Francisella tularensis to be wholly or partially removedfrom the body by removal of hydrated lung mucous secretions hydratedthrough the action of the sodium channel blocker.

The Category B and C bacteria most widely believed to have the potentialto infect by the aerosol route include gram negative bacteria such asBrucella species, Burkholderia pseudomallei, Burkholderia mallei,Coxiella burnetii, and select Rickettsia spp. Each of these agents isbelieved to be capable of causing infections following inhalation ofsmall numbers of organisms. Brucella spp. may cause brucellosis. Four ofthe six Brucella spp., B. suis, B. melitensis, B. abortus and B. canis,are known to cause brucellosis in humans. Burkholderia pseudomallei maycause melioidosis in humans and other mammals and birds. Burkholderiamallei, is the organism that causes glanders, normally a disease ofhorses, mules and donkeys but infection following aerosol exposure hasbeen reported, according to NIAID. Coxiella burnetii, may cause Q feverand is highly infectious. Infections have been reported throughaerosolized bacteria and inhalation of only a few organisms can causeinfections. R. prowazekii, R. rickettsii, R. conorrii and R. typhi havebeen found to have low-dose infectivity via the aerosol route.

Methods are provided of prophylactically treating one or moreindividuals exposed or potentially exposed to aerosolized gram negativebacteria such as Brucella species, Burkholderia pseudomallei,Burkholderia mallei, Coxiella burnetii, and select Rickettsia sppcomprising the administration of a sodium channel blocker. Theadministration of an effective amount of a sodium channel blocker willfunction to allow the aerosolized gram negative bacteria to be wholly orpartially removed from the body by removal of hydrated lung mucoussecretions hydrated through the action of the sodium channel blocker.

A number of typically arthropod-borne viruses are believed to pose asignificant threat as potential bioterrorist weapons due to theirextreme infectivity following aerosolized exposure. These virusesinclude arboviruses which are important agents of viral encephalitidesand hemorrhagic fevers. Such viruses may include alphaviruses such asVenezuelan equine encephalitis virus, eastern equine encephalitis virusand western equine encephalitis virus. Other such viruses may includeflaviviruses such as West Nile virus, Japanese encephalitis virus,Kyasanur forest disease virus, tick-borne encephalitis virus complex andyellow fever virus. An additional group of viruses which may pose athreat include bunyaviruses such as California encephalitis virus, or LaCrosse virus, Crimean-Congo hemorrhagic fever virus. According to theNIAID, vaccines or effective specific therapeutics are available foronly a very few of these viruses. In humans, arbovirus infection isusually initially asymptomatic or causes nonspecific flu-like symptomssuch as fever, aches and fatigue.

An embodiment of the present invention provides a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to aerosolized arboviruses comprising the administration of asodium channel blocker. The administration of an effective amount of asodium channel blocker will function to allow the arboviruses to bewholly or partially removed from the body by removal of hydrated lungmucous secretions hydrated through the action of the sodium channelblocker.

Certain category B toxins such as ricin toxin from Ricinus communis,epsilon toxin of Clostridium perfringens and Staphylococcal enterotoxinB, also are viewed as potential bioterrorism tools. Each of these toxinsmay be delivered to the environment or population by inhalationalexposure to aerosols. Low dose inhalation of ricin toxin may cause noseand throat congestion and bronchial asthma while higher doseinhalational exposure caused severe pneumonia, acute inflammation anddiffuse necrosis of the airways in nonhuman primates. Clostridiumperfringens is an anaerobic bacterium that can infect humans andanimals. Five types of bacteria exist that produce four major lethaltoxins and seven minor toxins, including alpha toxin, associated withgas gangrene, beta toxin, responsible for necrotizing enteritis, andepsilon toxin, a neurotoxin that leads to hemorrhagic enteritis in goatsand sheep. Inhalation of Staphylococcus aureus has resulted in extremelyhigh fever, difficulty breathing, chest pain and headache.

An embodiment of the present invention provides a method ofprophylactically treating one or more individuals exposed or potentiallyexposed to aerosolized toxins comprising the administration of a sodiumchannel blocker. The administration of an effective amount of a sodiumchannel blocker will function to allow the aerosolized toxins to bewholly or partially removed from the body by removal of hydrated lungmucous secretions hydrated through the action of the sodium channelblocker.

Mycobacterium tuberculosis bacteria causes tuberculosis and is spread byairborne droplets expelled from the lungs when a person withtuberculosis coughs, sneezes or speaks. An embodiment of the presentinvention provides a method of prophylactically treating one or moreindividuals exposed or potentially exposed to Mycobacterium tuberculosisbacteria comprising the administration of a sodium channel blocker. Theadministration of an effective amount of a sodium channel blocker willfunction to allow the Mycobacterium tuberculosis bacteria to be whollyor partially removed from the body by removal of hydrated lung mucoussecretions hydrated through the action of the sodium channel blocker.

The methods disclosed may also be used against more common pathogenssuch as influenza viruses, rhinoviruses, adenoviruses and respiratorysyncytial viruses (RSV). An embodiment of the present invention providesa method of prophylactically or therapeutically treating one or moreindividuals exposed or potentially exposed to one of these virusescomprising the administration of a sodium channel blocker. Theadministration of an effective amount of a sodium channel blocker willfunction to allow the virus to be wholly or partially removed from thebody by removal of hydrated lung mucous secretions hydrated through theaction of the sodium channel blocker.

The methods of the present invention may further be used against thevirus believed to be responsible for SARS, the coronavirus. Severe acuterespiratory syndrome is a respiratory illness that is believed to spreadby person-to-person contact, including when someone coughs or sneezesdroplets containing the virus onto others or nearby surfaces. The CDCcurrently believes that it is possible that SARS can be spread morebroadly through the air or by other ways that are not currently known.Typically, SARS begins with a fever greater than 100.4° F. Othersymptoms include headache and body aches. After two to seven days, SARSpatients may develop a dry cough and have trouble breathing.

To the extent SARS is caused by an airborne pathogen, the presentinvention provides a method of prophylactically treating one or moreindividuals exposed or potentially exposed to the SARS virus comprisingthe administration of a sodium channel blocker. The administration of aneffective amount of a sodium channel blocker will function to allow thevirus to be wholly or partially removed from the body by removal ofhydrated lung mucous secretions hydrated through the action of thesodium channel blocker.

The compounds of formulas (I), (II) and (III) may be synthesizedaccording to procedures known in the art. A representative syntheticprocedure is shown in the scheme below:

These procedures are described in, for example, E. J. Cragoe, “TheSynthesis of Amiloride and Its Analogs” (Chapter 3) in Amiloride and ItsAnalogs, pp. 25-36, incorporated herein by reference. Other methods ofpreparing the compounds are described in, for example, U.S. 3,313,813,incorporated herein by reference. See in particular Methods A, B, C, andD described in U.S. Pat. No. 3,313,813. Other methods useful for thepreparation of these compounds, are described in, for example, U.S.Provisional Applications 60/495,725, filed Aug. 19, 2003, 60/495,712,filed Aug. 19, 2003 and 60/495,720, filed Aug. 19, 2003, incorporatedherein by reference. Several assays may be used to characterize thecompounds of the present invention. Representative assays are discussedbelow.

In Vitro Measure of Sodium Channel Blocking Activity and Reversibility

One assay used to assess mechanism of action and/or potency of thecompounds of the present invention involves the determination of lumenaldrug inhibition of airway epithelial sodium currents measured undershort circuit current (I_(SC)) using airway epithelial monolayersmounted in Ussing chambers. Cells obtained from freshly excised human,dog, sheep or rodent airways are seeded onto porous 0.4 micron Snapwell™Inserts (CoStar), cultured at air-liquid interface (ALI) conditions inhormonally defined media, and assayed for sodium transport activity(I_(SC)) while bathed in Krebs Bicarbonate Ringer (KBR) in Usingchambers. All test drug additions are to the lumenal bath with half-logdose addition protocols (from 1×10⁻¹¹ M to 3×10⁻⁵ M), and the cumulativechange in I_(SC) (inhibition) recorded. All drugs are prepared indimethyl sulfoxide as stock solutions at a concentration of 1×10⁻² M andstored at −20° C. Eight preparations are typically run in parallel; twopreparations per run incorporate amiloride and/or benzamil as positivecontrols. After the maximal concentration (5×10⁻⁵ M) is administered,the lumenal bath is exchanged three times with fresh drug-free KBRsolution, and the resultant I_(SC) measured after each wash forapproximately 5 minutes in duration. Reversibility is defined as thepercent return to the baseline value for sodium current after the thirdwash. All data from the voltage clamps are collected via a computerinterface and analyzed off-line.

Dose-effect relationships for all compounds are considered and analyzedby the Prism 3.0 program. IC₅₀ values, maximal effective concentrations,and reversibility are calculated and compared to amiloride and benzamilas positive controls.

Pharmacological Assays of Absorption

(1) Apical Disappearance Assay

Bronchial cells (dog, human, sheep, or rodent cells) are seeded at adensity of 0.25'10⁶/cm² on a porous Transwell-Col collagen-coatedmembrane with a growth area of 1.13 cm² grown at an air-liquid interfacein hormonally defined media that promotes a polarized epithelium. From12 to 20 days after development of an air-liquid interface (ALI) thecultures are expected to be >90% ciliated, and mucins will accumulate onthe cells. To ensure the integrity of primary airway epithelial cellpreparations, the transepithelial resistance (R_(t)) and transepithelialpotential differences (PD), which are indicators of the integrity ofpolarized nature of the culture, are measured. Human cell systems arepreferred for studies of rates of absorption from apical surfaces. Thedisappearance assay is conducted under conditions that mimic the “thin”films in vivo (˜25 μl) and is initiated by adding experimental sodiumchannel blockers or positive controls (amiloride, benzamil, phenamil) tothe apical surface at an initial concentration of 10 μM. A series ofsamples (5 μl volume per sample) is collected at various time points,including 0, 5, 20, 40, 90 and 240 minutes. Concentrations aredetermined by measuring intrinsic fluorescence of each sodium channelblocker using a Fluorocount Microplate Flourometer or HPLC. Quantitativeanalysis employs a standard curve generated from authentic referencestandard materials of known concentration and purity. Data analysis ofthe rate of disappearance is performed using nonlinear regression, onephase exponential decay (Prism V 3.0).

2. Confocal Microscopy Assay of Amiloride Congener Uptake

Virtually all amiloride-like molecules fluoresce in the ultravioletrange. This property of these molecules may be used to directly measurecellular update using x-z confocal microscopy. Equimolar concentrationsof experimental compounds and positive controls including amiloride andcompounds that demonstrate rapid uptake into the cellular compartment(benzamil and phenamil) are placed on the apical surface of airwaycultures on the stage of the confocal microscope. Serial x-z images areobtained with time and the magnitude of fluorescence accumulating in thecellular compartment is quantitated and plotted as a change influorescence versus time.

3. In vitro Assays of Compound Metabolism

Airway epithelial cells have the capacity to metabolize drugs during theprocess of transepithelial absorption. Further, although less likely, itis possible that drugs can be metabolized on airway epithelial surfacesby specific ectoenzyme activities. Perhaps more likely as anecto-surface event, compounds may be metabolized by the infectedsecretions that occupy the airway lumens of patients with lung disease,e.g. cystic fibrosis. Thus, a series of assays is performed tocharacterize the compound metabolism that results from the interactionof test compounds with human airway epithelia and/or human airwayepithelial lumenal products.

In the first series of assays, the interaction of test compounds in KBRas an “ASL” stimulant are applied to the apical surface of human airwayepithelial cells grown in the T-Col insert system. For most compounds,metabolism (generation of new species) is tested for using highperformance liquid chromatography (HPLC) to resolve chemical species andthe endogenous fluorescence properties of these compounds to estimatethe relative quantities of test compound and novel metabolites. For atypical assay, a test solution (25 μl KBR, containing 10 μM testcompound) is placed on the epithelial lumenal surface. Sequential 5 to10 μl samples are obtained from the lumenal and serosal compartments forHPLC analysis of (1) the mass of test compound permeating from thelumenal to serosal bath and (2) the potential formation of metabolitesfrom the parent compound. In instances where the fluorescence propertiesof the test molecule are not adequate for such characterizations,radiolabeled compounds are used for these assays. From the HPLC data,the rate of disappearance and/or formation of novel metabolite compoundson the lumenal surface and the appearance of test compound and/or novelmetabolite in the basolateral solution is quantitated. The data relatingthe chromatographic mobility of potential novel metabolites withreference to the parent compound are also quantitated.

To analyze the potential metabolism of test compounds by CF sputum, a“representative” mixture of expectorated CF sputum obtained from 10 CFpatients (under IRB approval) has been collected. The sputum has been besolubilized in a 1:5 mixture of KBR solution with vigorous vortexing,following which the mixture was split into a “neat” sputum aliquot andan aliquot subjected to ultracentrifugation so that a “supernatant”aliquot was obtained (neat=cellular; supernatant=liquid phase). Typicalstudies of compound metabolism by CF sputum involve the addition ofknown masses of test compound to “neat” CF sputum and aliquots of CFsputum “supernatant” incubated at 37° C., followed by sequentialsampling of aliquots from each sputum type for characterization ofcompound stability/metabolism by HPLC analysis as described above. Asabove, analysis of compound disappearance, rates of formation of novelmetabolites, and HPLC mobilities of novel metabolites are thenperformed.

4. Pharmacological Effects and Mechanism of Action of the Drug inAnimals

The effect of compounds for enhancing mucociliary clearance (MCC) can bemeasured using an in vivo model described by Sabater et al., Journal ofApplied Physiology, 1999, pp. 2191-2196, incorporated herein byreference.

Animal Preparation: Adult ewes (ranging in weight from 25 to 35 kg) wererestrained in an upright position in a specialized body harness adaptedto a modified shopping cart. The animals' heads were immobilized andlocal anesthesia of the nasal passage was induced with 2% lidocaine. Theanimals were then nasally intubated with a 7.5 mm internal diameterendotracheal tube (ETT). The cuff of the ETT was placed just below thevocal cords and its position was verified with a flexible bronchoscope.After intubation the animals were allowed to equilibrate forapproximately 20 minutes prior to initiating measurements of mucociliaryclearance.

Administration of Radio-aerosol: Aerosols of ^(99m)Tc-Human serumalbumin (3.1 mg/ml; containing approximately 20 mCi) were generatedusing a Raindrop Nebulizer which produces a droplet with a medianaerodynamic diameter of 3.6 μm. The nebulizer was connected to adosimetry system consisting of a solenoid valve and a source ofcompressed air (20 psi). The output of the nebulizer was directed into aplastic T connector; one end of which was connected to the endotrachealtube, the other was connected to a piston respirator. The system wasactivated for one second at the onset of the respirator's inspiratorycycle. The respirator was set at a tidal volume of 500 mL, aninspiratory to expiratory ratio of 1:1, and at a rate of 20 breaths perminute to maximize the central airway deposition. The sheep breathed theradio-labeled aerosol for 5 minutes. A gamma camera was used to measurethe clearance of ^(99m)Tc-Human serum albumin from the airways. Thecamera was positioned above the animal's back with the sheep in anatural upright position supported in a cart so that the field of imagewas perpendicular to the animal's spinal cord. External radio-labeledmarkers were placed on the sheep to ensure proper alignment under thegamma camera. All images were stored in a computer integrated with thegamma camera. A region of interest was traced over the imagecorresponding to the right lung of the sheep and the counts wererecorded. The counts were corrected for decay and expressed aspercentage of radioactivity present in the initial baseline image. Theleft lung was excluded from the analysis because its outlines aresuperimposed over the stomach and counts can be swallowed and enter thestomach as radio-labeled mucus.

Treatment Protocol (Assessment of activity at t-zero): A baselinedeposition image was obtained immediately after radio-aerosoladministration. At time zero, after acquisition of the baseline image,vehicle control (distilled water), positive control (amiloride), orexperimental compounds were aerosolized from a 4 ml volume using a PariLC JetPlus nebulizer to free-breathing animals. The nebulizer was drivenby compressed air with a flow of 8 liters per minute. The time todeliver the solution was 10 to 12 minutes. Animals were extubatedimmediately following delivery of the total dose in order to preventfalse elevations in counts caused by aspiration of excess radio-tracerfrom the ETT. Serial images of the lung were obtained at 15-minuteintervals during the first 2 hours after dosing and hourly for the next6 hours after dosing for a total observation period of 8 hours. Awashout period of at least 7 days separated dosing sessions withdifferent experimental agents.

Treatment Protocol (Assessment of Activity at t-4 hours): The followingvariation of the standard protocol was used to assess the durability ofresponse following a single exposure to vehicle control (distilledwater), positive control compounds (amiloride or benzamil), orinvestigational agents. At time zero, vehicle control (distilled water),positive control (amiloride), or investigational compounds wereaerosolized from a 4 ml volume using a Pari LC JetPlus nebulizer tofree-breathing animals. The nebulizer was driven by compressed air witha flow of 8 liters per minute. The time to deliver the solution was 10to 12 minutes. Animals were restrained in an upright position in aspecialized body harness for 4 hours. At the end of the 4-hour periodanimals received a single dose of aerosolized ^(99m)Tc-Human serumalbumin (3.1 mg/ml; containing approximately 20 mCi) from a RaindropNebulizer. Animals were extubated immediately following delivery of thetotal dose of radio-tracer. A baseline deposition image was obtainedimmediately after radio-aerosol administration. Serial images of thelung were obtained at 15-minute intervals during the first 2 hours afteradministration of the radio-tracer (representing hours 4 through 6 afterdrug administration) and hourly for the next 2 hours after dosing for atotal observation period of 4 hours. A washout period of at least 7 daysseparated dosing sessions with different experimental agents.

Statistics: Data were analyzed using SYSTAT for Windows, version 5. Datawere analyzed using a two-way repeated ANOVA (to assess overalleffects), followed by a paired t-test to identify differences betweenspecific pairs. Significance was accepted when P was less than or equalto 0.05. Slope values (calculated from data collected during the initial45 minutes after dosing in the t-zero assessment) for mean MCC curveswere calculated using linear least square regression to assessdifferences in the initial rates during the rapid clearance phase.

EXAMPLES

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

Preparation of Sodium Channel Blockers

Materials and methods. All reagents and solvents were purchased fromAldrich Chemical Corp. and used without further purification. NMRspectra were obtained on either a Bruker WM 360 (¹H NMR at 360 MHz and¹³C NMR at 90 MHz) or a Bruker AC 300 (¹H NMR at 300 MHz and ¹³C NMR at75 MHz). Flash chromatography was performed on a Flash Elute system fromElution Solution (PO Box 5147, Charlottesville, Va. 22905) charged witha 90 g silica gel cartridge (40 M FSO-0110-040155, 32-63 μm) at 20 psi(N₂). GC-analysis was performed on a Shimadzu GC-17 equipped with aHeliflex Capillary Colunm (Alltech); Phase: AT-1, Length: 10 meters, ID:0.53 mm, Film: 0.25 micrometers. GC Parameters: Injector at 320° C.,Detector at 320° C., FID gas flow: H₂ at 40 ml/min., Air at 400 ml/min.Carrier gas: Split Ratio 16:1, N₂ flow at 15 ml/min., N₂ velocity at 18cm/sec. The temperature program is 70° C. for 0-3 min, 70-300° C. from3-10 min, 300° C. from 10-15 min.

HPLC analysis was performed on a Gilson 322 Pump, detector UV/Vis-156 at360 nm, equipped with a Microsorb MV C8 column, 100 A, 25 cm. Mobilephase: A=acetonitrile with 0.1% TFA, B=water with 0.1% TFA. Gradientprogram: 95:5 B:A for 1 min, then to 20:80 B:A over 7 min, then to 100%A over 1 min, followed by washout with 100% A for 11 min, flow rate: 1ml/min.

The following examples depict the synthesis of compounds according toFormula I.

FORMULA I EXAMPLES

Example 1 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)guanidinehydrochloride (PSA 17926)

{4-[4-(3-Cyanopropoxy)phenyl]butyl}carbamic acid benzyl ester (2)

A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester 1(2.00 g, 6.70 mmol), 4-bromobutyronitrile (0.70 mL, 6.70 mmol), andpotassium carbonate (1.00 g, 7.4 mmol) in DMF (10 mL), was stirred at65° C. for 16 h. Solvent was removed by rotary evaporation and theresidue was taken up in ethyl acetate, washed with water and brine, andconcentrated under vacuum. The crude product was purified by flashsilica gel column chromatography eluting with ethyl acetate/CH₂Cl₂ (1:9,v/v) to give the desired product 2 as a white solid (1.80 g, 75% yield).¹H NMR (300 MHz, CDCl₃) δ 1.56 (m, 4H), 2.15 (m, 2H), 2.55 (m, 4H), 3.15(m, 2H), 4.00 (m, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.80 (d, 2H), 7.05(d, 2H), 7.30 (m, 5H). m/z (ESI): 367 [C₂₂H₂₆N₂O₃+H]⁺.

(4-{4-[3-(1H-Tetrazol-5-yl)propoxy]phenyl}butyl)carbamic acid benzylester (3)

A mixture of {4-[4-(3-cyanopropoxy)phenyl]butyl}carbamic acid benzylester 2 (0.90 g, 2.5 mmol), sodium azide (0.50 g, 7.5 mmol), andammonium chloride (0.40 g, 7.5 mmol) in DMF (7 mL), was stirred at 120°C. for 16 h. Inorganics were removed by vacuum filtration. The filtratewas diluted with ethyl acetate, and washed with water and brine. Theorganic solution was dried over Na₂SO₄, filtered and concentrated. Theresidue was taken up in ethyl acetate (5 mL) and diluted with hexanes(10 mL). Solid precipitates were collected by suction filtration andpurified by flash silica gel column chromatography eluting withmethanol/dichloromethane (1:50, v/v) to give the desired product 3 as awhite solid (0.78 g, 76% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.51 (m, 4H),2.20 (m, 2H), 2.50 (m, 2H), 3.10 (m, 4H), 4.00 (m, 2H), 5.00 (s, 2H),6.75 (d, 2H), 7.05 (d, 2H), 7.30 (m, 5H). m/z (ESI): 410[C₂₂H₂₇N₅O₃+H]⁺.

4-{4-[3-(1H-Tetrazol-5-yl)propoxy]phenyl}butylamine (4)

A solution of (4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)carbamicacid benzyl ester 3 (0.30 g, 0.73 mmol) in methanol (20 ML) anddichloromethane (5 mL) was stirred at room temperature overnight underhydrogen atmosphere in the presence of 10% palladium-on-carbon catalyst(0.1 g, 50% wet). The catalyst was removed by suction filtration, andthe filtrate was concentrated in vacuo to give the desired product 4 asa white solid (200 mg, 99% yield) which was used for the next stepwithout further purification. m/z (ESI): 276 [C₁₄H₂₁N₅O+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(1H-tetrazol-5-yl)-propoxy]phenyl}butyl)guanidinehydrochloride (5, PSA 17926)

A solution of 4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butylamine 4 (100mg, 0.36 mmol) and triethylamine (0.15 mL, 0.39 mmol) in absoluteethanol (2 mL) was stirred at 60° C. for 5 min, after which1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothioureahydriodide (150 mg, 0.39 mmol) was added in one portion. The reactionmixture was stirred at that temperature for 4 h and then cooled to roomtemperature. The reaction mixture was concentrated by rotaryevaporation. The crude residue was washed with water and filtered. Thefilter cake was further washed with dichloromethane. A dark yellow solid(140 mg, 80% yield) thus obtained was slurried in a mixture of methanoland dichloromethane (5/95, v/v). The solid was collected by suctionfiltration, and 40 mg of such solid was mixed with 3% aqueous HCl (4mL). The mixture was sonicated, stirred at room temperature for 15 minand filtered. The filter cake was dried under high vacuum to giveN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)guanidinehydrochloride (5, PSA 17926) as a yellow solid. mp 125-127° C.(decomposed). ¹H NMR (300 MHz, CD₃OD) δ 1.70 (m, 4H), 2.22 (m, 2H), 2.60(m, 2H), 3.10 (m, 2H), 4.00 (m, 2H), 6.70 (d, 2H), 7.09 (d, 2H). m/z(ESI): 488 [C₂₀H₂₆ClN₁₁O₂+H]⁺.

Example 2 Synthesis of dimethylthiocarbamic acidO-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenyl)ester (PSA 17846)

2-[4-(4-Hydroxyphenyl)butyl]isoindole-1,3-dione (8)

A mixture of 4-(4-aminobutyl)phenol hydrobromide 6 (8.2 g, 33.5mmol),phthalic anhydride 7 (5.0 g, 33.8 mmol), and triethylamine (4.6 mL, 33.5mmol) in chloroform (50 mL) was stirred at reflux for 18 h, cooled toroom temperature and concentrated by rotary evaporation. The residue wasdissolved in acetic acid (50 mL) and stirred at 100° C. for 3 h. Solventwas evaporated and the resulting residue was purified by flash silicagel column chromatography eluting with CH₂Cl₂/EtOAc/hexanes (8:1:1, v/v)to give the desired product 8 as a white powder (4.1 g, 41% yield). ¹HNMR (300 MHz, DMSO-d₆) 6 1.57 (m, 4H), 2.46 (m, 2H), 3.58 (m, 2H), 6.64(d, 2H), 6.95 (d, 2H), 7.82 (m, 4H), 9.12 (s, 1H). m/z (ESI): 296[C₁₈H₁₇NO₃+H]⁺.

Dimethylthiocarbamic acidO-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-phenyl} ester (9)

A suspension of sodium hydride (60% in mineral oil, 0.44 g, 0.11 mmol)in anhydrous DMF (10 mL) was cooled to 0° C. and added to a solution of2-[4-(4-hydroxyphenyl)-butyl]isoindole-1,3-dione 8 (2.95 g, 10 mmol) inDMF (15 mL). The mixture was stirred at 0° C. for 30 min and then atroom temperature for an additional one hour. A solution ofdimethylthiocarbamic acid chloride (1.35 g, 11 mmol) in DMF (10 mL) wasthen added. The reaction mixture was stirred at room temperature firstfor 16 h and then at 50° C. for 1 h, cooled back to room temperature andquenched with methanol (10 mL). The mixture was concentrated undervacuum and the residue was purified by flash silica gel columnchromatography eluting with CH₂Cl₂/hexanes/EtOAc (10:1:0.2, v/v) to givethe desired product 9 as a yellowish solid (2.27 g, 59% yield). ¹H NMR(300 MHz, CDCl₃) δ 1.72 (m, 4H), 2.67 (m, 2H), 3.33 (s, 3H), 3.45 (s,3H), 3.71 (m, 2H), 6.95 (d, 2H), 7.18 (d, 2H), 7.70 (m, 2H), 7.84 (m,2H). m/z (ESI): 383 [C₂₁H₂₂N₂O₃S+H]⁺.

Dimethylthiocarbamic acid O-[4-(4-aminobutyl)phenyl] ester (10)

A mixture of dimethylthiocarbamic acidO-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-butyl]phenyl} ester 9 (0.30g, 0.80 mmol) and methylamine (2M in methanol, 10 mL, 20 mmol) wasstirred at room temperature overnight. Solvent was removed by rotaryevaporation and the residue was purified by flash silica gel columnchromatography (Biotage) eluting with chloroform/methanol/concentratedammonium hydroxide (10:1:0.1, v/v) to give dimethylthiocarbamic acidO-[4-(4-aminobutyl)phenyl] ester (10) as a clear colorless oil (118 mg,46% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.70 (m, 4H), 2.70 (m, 4H), 3.34(s, 3H), 3.46 (s, 3H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (ESI): 253[Cl₃H₂₀N₂OS+H]⁺.

Dimethylthiocarbamic acidO-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenyl)ester (11, PSA 17846)

A solution of dimethylthiocarbamic acid O-[4-(4-aminobutyl)phenyl] ester10 (115 mg, 0.45 mmol), triethylamine (0.30 mL, 2.2 mmol), and1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (175 mg, 0.45 mmol) in anhydrous THF (6 mL) was stirred atreflux for 3 h and then cooled to room temperature. The reaction mixturewas concentrated by rotary evaporation. The crude residue was purifiedby flash silica gel column chromatography (Biotage) eluting withchloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) togive the desired product 11 as a yellow solid (180 mg, 86% yield). mp102-105° C. ¹H NMR (300 MHz, CD₃OD) δ 1.70 (m, 4H), 2.65 (m, 2H), 3.20(m, 2H), 3.30 (s, 3H), 3.40 (s, 3H), 6.95 (d, 2H), 7.20 (d, 2H). m/z(ESI): 465 [Cl₉H₂₅ClN₈O₂S+H]⁺.

Example 3 Synthesis of(2S)-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-butyl}benzenesulfonylamino)-3-methylbutyramide(PSA 19008)

4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride(13)

2-(4-Phenylbutyl)isoindole-1,3-dione 12 (1.9 g, 6.8 mmol) was added tochlorosulfonic acid (10 mL, 138 mmol) at 0° C. and the mixture wasstirred for 1 h at the temperature. After storing in refrigerator at −5°C. overnight, the reaction mixture was poured onto crushed ice (100 g)and precipitates were collected by a suction filtration and dried underhigh vacuum to afford the desired product 13 (2.48 g, 99% yield). ¹H NMR(300 MHz, CDCl₃) δ 1.70 (m, 4H), 2.78 (m, 2H), 3.70 (m, 2H), 7.40 (d,2H) 7.70 (d, 2H), 7.85 (d, 2H), 7.95 (d, 2H).

(2S)-{4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonylamino}-3-methylbutyramide(14)

4-[4-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)butyl]benzenesulfonyl chloride13 (0.45 g, 1.19 mmol) was dissolved in dry DMF (5 mL), and added to asolution of N-methylmorpholine (3 mL) and (2S)-amino-3-methylbutyramide(0.18 g, 1.19 mmol) in DMF (10 mL). The reaction mixture was stirred atroom temperature for 66 h. Solvent was removed by rotary evaporation andthe residue was purified by flash silica gel chromatography eluting withchloroform/methanol/concentrated ammonium hydroxide (15:1:0.1, v/v) togive the desired product 14 as a white powder (0.41 g, 73% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 0.72 (d, 3H), 0.76 (d, 3H), 1.77 (m, 4H), 1.79(m, 1H), 2.68 (m, 2H), 3.40 (m, 1H), 3.60 (m, 2H), 6.92 (s, 1H), 7.21(s, 1H), 7.34 (d, 2H) 7.50 (d, 1H), 7.65 (d, 2H), 7.82 (m, 4H).

(2S)-[4-(4-Aminobutyl)benzenesulfonylamino]-3-methylbutyramide (15)

A mixture of(2S)-{4-[4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)butyl]-benzenesulfonylamino}-3-methylbutyramide14 (0.40 g, 0.87 mmol) and methylamine (2 M in methanol, 20 mL, 40 mmol)was stirred at room temperature overnight. Solvent was removed by rotaryevaporation and the residue was purified by flash silica gel columnchromatography eluting with chloroform/methanol/concentrated ammoniumhydroxide (3:1:0.1, v/v) to give(2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methyl-butyramide (15) asa white powder (156 mg, 54% yield). ¹H NMR (300 MHz, CD₃OD) δ 0.85 (d,3H), 0.87 (d, 3H), 1.66 (m, 4H), 1.90 (m, 1H), 2.69 (m, 4H), 3.51 (d,1H), 7.35 (d, 2H) 7.75 (d, 2H). m/z (ESI): 328 [Cl₅H₂₅N₃O₃S+H]⁺.

(2S)-(4-{4-[NM-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-benzenesulfonylamino)-3-methylbutyramide(16, PSA 19008)

A solution of(2S)-[4-(4-aminobutyl)benzenesulfonylamino]-3-methylbutyramide 15 (156mg, 0.47 mmol), diisopropylethylamine (0.60 mL, 3.0 mmol), and1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (230 mg, 0.61 mmol) in absolute ethanol (8 mL) was stirred at70° C. for 5 h and then cooled to room temperature. The reaction mixturewas concentrated by rotary evaporation. The crude residue was washedwith water, filtered and the crude solid product was purified by flashsilica gel column chromatography eluting withchloroform/methanol/concentrated ammonium hydroxide (5:1:0.1, v/v) togive the desired product as a yellow solid (137 mg, 54% yield). Part ofthe solid (86 mg) was further purified by semi-preparative HPLC(acetonitrile/water/0.1% TFA) to give the analytical pure sample whichwas then co-evaporated with 5% aqueous HCl to give the hydrochloridesalt 16. mp 154-156° C. (decomposed). ¹H NMR (300 MHz, CD₃OD) δ 0.85 (d,3H), 0.86 (d, 3H), 1.70 (m, 4H), 1.90 (m, 1H), 2.75 (m, 2H), 3.32 (m,2H), 3.52 (d, 1H), 7.35 (d, 2H), 7.75 (d, 2H). m/z (ESI): 540[C₂₁H₃₀ClN₉O₄S+H]⁺. [α]_(D) ²⁵+5.20 (c 0.50, MeOH).

Example 4 Synthesis of 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-butyl}phenoxy)-N-phenylacetamide(PSA 17482)

4-(4-Phenylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester (18)

A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy] acetic acid (300mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol)and EDC.HCl (320 mg, 1.70 mmol) in CH₂Cl₂ (30 mL) was stirred at roomtemperature for 66 h. The reaction mixture was concentrated under vacuumand the residue was subjected to flash silica gel column chromatographyeluting with methanol/CH₂Cl₂ (1:99, v/v) to give the desired amide 18 asa white solid (360 mg, 99% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.55 (m,4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s,2H), 6.88 (d, 2H), 7.15 (m, 3H), 7.35 (m, 7H), 7.58 (s, 2H), 8.25 (s,1H). m/z (ESD): 433 [C₂₆H₂₈N₂O₄+H]⁺.

2-[4-(4-Aminobutyl)phenoxy]-N-phenylacetamide (19)

A solution of [4-(4-phenylcarbamoylmethoxyphenyl)butyl]carbamic acidbenzyl ester 18 (0.30 g, 0.69 mmol) in ethanol (10 mL), THF (6 mL), andacetic acid (2 mL) was stirred at room temperature for 2 h underhydrogen atmosphere in the presence of 10% Pd/C catalyst (0.2 g, 50%wet). The catalyst was removed by suction filtration and the filtratewas concentrated in vacuo. The residue was purified by flash silica gelcolumn chromatography eluting with CH₂Cl₂/methanol/concentrated ammoniumhydroxide (30:1:0, 30:1:0.3, v/v) to give the desired amine 19 as awhite solid (200 mg, 97% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.60 (m, 4H),2.55 (m, 2H), 2.70 (m, 2H), 4.60 (s, 2H), 6.88 (d, 2H), 7.15 (m, 3H),7.35 (m, 2H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (EST): 299[Cl₈H₂₂N₂O₂+H]⁺.

2-(4-{4-[NA-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenylacetamide(20, PSA 17482)

A solution of 2-[4-(4-aminobutyl)phenoxy]-N-phenylacetamide 19 (100 mg,0.35 mmol) and triethylamine (0.14 mL, 1.00 mmol) in absolute ethanol (2mL) was stirred at 60° C. for 30 min, after which1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothioureahydriodide (140 mg, 0.37 mmol) was added in one portion. The reactionmixture was stirred at that temperature for 4 h, cooled to roomtemperature, and concentrated by rotary evaporation. The crude residuewas triturated with water and filtered. The filter cake was purified byflash silica gel column chromatography eluting withdichloromethane/methanol/concentrated ammonium hydroxide (500:10:0,500:10:1, 200:10:1, v/v) to give2-(4-{4-[N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenylacetamide(20, PSA 17482) as a yellow solid (120 mg, 67% yield). mp 168-170° C. ¹HNMR (300 MHz, DMSO-d₆) δ 1.55 (m, 4H), 2.55 (m, 2H), 3.16 (m, 2H), 4.65(s, 2H), 6.60 (br s, 2H), 6.90 (d, 2H), 7.08 (m, 2H), 7.15 (d, 2H), 7.30(m, 5H), 7.60 (d, 2H), 9.00 (br s, 1H), 10.00 (br s, 1H). m/z (ESI): 511[C₂₄H₂₇ClN₈O₃+H]⁺.

Example 5 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(1H-imidazol-2-yl)propoxy]phenyl}butyl)guanidine(PSA 23022)

4-{4-[3-(1H-Imidazol-2-yl)propoxylphenyl}butylamine (21)

Compound 2 (0.156 g, 0.425 mmol) was dissolved in anhydrous ethanol (10mL). To the solution was bubbled anhydrous HCl gas for 3 min. Thereaction vessel was sealed and the mixture was stirred at roomtemperature for 48 h, and then concentrated to dryness under vacuum. Theresulting residue was dissolved in anhydrous methanol (5 mL). To thenewly formed solution was added 2,2-dimethoxyethylamine (0.097 mL, 0.891mmol) in one portion. After stirring at room temperature overnight,temperature was raised to reflux which was maintained for another 3 hbefore the mixture was cooled to ambient temperature. Solvent wasremoved under vacuum and the residue was treated with 1.2 N HCl aqueoussolution at 80° C. for 2 hours. The mixture was then cooled to ambienttemperature again and neutralized to pH 9 with powder K₂CO₃. Water wascompletely removed under vacuum and the residue was dissolved inmethanol. The methanol solution was loaded onto silica gel, and theproduct was eluted with a mixture of concentrated ammoniumhydroxide/MeOH/CH₂Cl₂ (1.8:18:81.2, v/v), affording the product 21 (27mg, 23% overall yield) as an off-white solid. ¹H NMR (300 MHz, CD₃OD): δ1.60 (m, 4H), 2.14 (m, 2H), 2.56 (t, 2H), 2.76 (t, 2H), 2.86 (t, 2H),3.94 (t, 2H), 6.79 (d, 2H), 6.91 (s, 2H), 7.08 (d, 2H). m/z (APCI): 274[Cl₆H₂₃N₃O+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-(4-(4-[3-(1H-imidazol-2-yl)propoxylphenyl}butyl)guanidine(22, PSA 23022)

Compound 21 (23 mg, 0.084 mmol) was dissolved in a mixture of ethanol (3mL) and Hunig's base (0.074 mL, 0.421 mmol) at 65° C. over 15 min. Tothe solution was added1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methlisothioureahydriodide (43 mg, 0.109 mmol) and the resulting mixture was stirred atthe above temperature for an additional 3 h before all liquid wasremoved under vacuum. The residue was chromatographed on silica gel,eluting with a mixture of concentrated ammoniumhydroxide/methanol/dichloromethane (1.5:15:63.5, v/v), to afford thedesired product 22 (34 mg, 83% yield) as a yellow solid. mp 123-126° C.(decomposed), ¹H NMR (300 MHz, CD₃OD): δ 1.62 (m, 4H), 2.14 (m, 2H),2.58 (t, 2H), 2.88 (t, 2H), 3.21(t, 2H), 3.94(t, 2H), 6.77 (d, 2H), 6.90(s, 2H), 7.06 (d, 2H). m/z (APCI): 486 [C₂₂H₂₈ClN₉O₂+H]⁺.

Example 6 Synthesis of2-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-butyl}phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide(PSA 16826)

[4-(4-{[N,N-Bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)butyl]carbamicacid benzyl ester (25)

A solution of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acidethyl ester 23 (0.3 g, 0.78 mmol), 2-(2-hydroxyethylamino)ethanol 24(0.15 mL, 1.6 mmol), and ethanol (20 mL) was heated at 70° C. for 72hours. Solvent was evaporated in vacuo. The residue was purified byflash chromatography (silica gel, dichloromethane/methanol, 100:5, v/v)to provide[4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamicacid benzyl ester 25 [0.19 g, 100% based on the recovered startingmaterial (0.13 g)] as a pale yellow solid. ¹H NMR (300 MHz, CD₃OD) δ1.65 (m, 4H), 2.50 (m, 2H), 3.20 (m, 2H), 3.55 (m, 4H), 3.75 (m, 4H),4.80 (s, 2H), 5.10 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H), 7.40 (m, 5H).m/z (ESI): 445 [C₂₄H₃₂N₂O₆+H]⁺.

2-[4-(4-Aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide (26)

To a degassed solution of[4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamicacid benzyl ester 25 (0.19 g, 0.43 mmol) in ethanol (4 mL) was added 10%palladium on activated carbon (0.1 g, 50% wet). The mixture washydrogenated overnight at atmospheric hydrogen. The catalyst wasfiltered through a pad of diatomaceous earth and the solvent wasevaporated in vacuo. The residue was purified by flash chromatography(silica gel, 20-5:1:0.1-1 dichloromethane/methanol/concentrated ammoniumhydroxide, v/v) to provide 26 (0.09 g, 72%) as a colorless oil. ¹H NMR(300 MHz, CD₃OD) δ 1.56 (m, 4H), 2.56 (t, 2H), 2.65 (t, 1H), 3.29 (m,1H), 3.55 (m, 4H), 3.72 (m, 4H), 4.90 (s, 2H), 6.86 (d, 2H), 7.09 (d,2H). m/z (ESI): 311 [C₁₆H₂₆N₂O₄+H]⁺.

2-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide(27, PSA 16826)

1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (0.13 g, 0.33 mmol) was added to a solution of2-[4-(4-aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide 26 (0.09g, 0.3 mmol), triethylamine (0.12 mL), and ethanol (1.7 mL). Thereaction mixture was stirred at 60° C. for 3 h. The solvent wasevaporated in vacuo. The residue was triturated with water and thenpurified by flash chromatography (silica gel, 20-10:1:0-0.2CH₂Cl₂/methanol/concentrated ammonium hydroxide, v/v) to provide2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide27 (0.1 g, 64%) as a yellow solid. mp 1 14-116° C. ¹H NMR (300 MHz,CD₃OD) δ 1.70 (m, 4H), 2.60 (m, 2H), 3.32 (m, 2H), 3.50 (m, 4H), 3.70(m, 4H), 4.81 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H). m/z (ESD): 523[C₂₂H₃₁ClN₈O₅+H]⁺.

Example 7 Synthesis of2-(4-{4-[N-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-butyl}phenoxy)-N,N-dimethylacetamidehydrochloride (PSA 16313)

[4-(4-Dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester(28)

A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid ethylester 23 (0.50 g, 1.3 mmol) and dimethylamine (2.0 M in THF, 10 mL, 20mmol) in a sealed tube was heated at 55° C. for 48 h. The solvent wasevaporated in vacuo. The residue was purified by flash chromatography(silica gel, ethyl acetate/CH₂Cl₂, 1:4, 1:3, v/v) to provide[4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 28(0.26 g, 52% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.55 (m,4H), 2.55 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 3.20 (m, 2H), 4.65 (s,2H), 5.08 (s, 2H), 6.80 (d, 2H), 7.05 (d, 2H), 7.35 (m, 5H).

2-[4-(4-Aminobutyl)phenoxy]-N,N-dimethylacetamide (29)

To a degassed solution of[4-(4-dimethylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester(28) (0.26 g, 0.68 mmol) in ethanol (10 mL) was added 10% palladium onactivated carbon (0.1 g, 50% wet). The mixture was stirred at roomtemperature overnight under atmospheric hydrogen. The catalyst wasfiltered through a pad of diatomaceous earth and the solvent wasevaporated in vacuo. The residue was purified by flash chromatography(silica gel, dichloromethane/methanol/concentrated ammonium hydroxide,100:5:1, v/v) to provide2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (100 mg, 60% yield)as a white solid. ¹H NMR (300 MHz, CD₃OD) δ 1.55 (m, 4H), 2.55 (m, 2H),2.66 (m, 2H), 2.90 (s, 3H), 3.05 (s, 3H), 4.70 (s, 2H), 6.80 (d, 2H),7.05 (d, 2H). m/z (ESI): 251 [Cl₄H₂₂N₂O₂+H]⁺.

2-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N,N-dimethylacetamidehydrochloride (30, PSA 16313)

A solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-dimethylacetamide 29 (67mg, 0.27 mmol) in absolute ethanol (1 mL) was stirred at 65° C. for 30min, after which1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (110 mg, 0.29 mmol) was added in one portion. The reactionmixture was stirred at that temperature for 3 h and then cooled to roomtemperature. The reaction mixture was concentrated by rotaryevaporation. The crude residue was triturated with water and filtered.The filter cake was purified by flash silica gel column chromatographyeluting with dichloromethane/methanol/concentrated ammonium hydroxide(200:10:0, 200:10:1, v/v) to give2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-dimethylacetamideas a yellow solid (35 mg, 28% yield). This solid was dissolved inmethanol (2 mL) and added to 4 N aqueous HCl (4 drops). Concentration invacuo gave2-(4-{4-[NA-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenoxy)-N,N-dimethylacetamidehydrochloride (30, PSA 16313). mp 130-132° C. (decomposed). ¹H NMR (300MHz, CD₃OD) δ 1.69 (m, 4H), 2.60 (m, 2H), 2.95 (s, 3H), 3.10 (s, 3H),3.35 (m, 2H), 4.75 (s, 2H), 6.80 (d, 2H), 7.10 (d, 2H). m/z (ESI): 463[C₂₀H₂₇ClN₈O₃+H]⁺.

Example 8 Synthesis of2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-butyl}phenoxy)-N-(1H-imidazol-2-yl)acetamidedihydrochloride (PSA 16437)

[4-(4-tert-Butoxycarbonylaminobutyl)phenoxy]acetic acid methyl ester(32)

A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid tert-butyl ester 31(1.00 g, 3.78 mmol), potassium carbonate (0.627 g, 4.54 mmol), sodiumiodide (0.567 g, 3.78 mmol), and methyl bromoacetate (0.40 mL, 4.21mmol) in anhydrous DMF (8 mL) was stirred at room temperature for 14 h.The reaction mixture was then diluted with ethyl acetate (100 mL) andhexanes (20 mL), washed with water (20 mL×4) and brine (30 mL), andconcentrated under reduced pressure to afford the desired product 32 asa yellow oil (1.28 g, 100% yield) which was used for the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 1.40 (s, 9H),1.41-1.65 (m, 4H), 2.49-2.60 (m, 2H), 3.02-3.16 (m, 2H), 3.79 (s, 3H),4.45 (br s, 1H), 4.59 (s, 2H), 6.79 (d, 2H), 7.05 (d, 2H). m/z (ESI):338 [C₁₈H₂₇NO₅+H]⁺.

[4-(4-tert-Butoxycarbonylaminobutyl)phenoxy]acetic acid (33)

A solution of [4-(4-tert-butoxycarbonylaminobutyl)phenoxy]acetic acidmethyl ester 32 (1.28 g, 3.78 mmol) in methanol (80 mL) was added withcrushed potassium hydroxide (2.50 g, 85%, 37.8 mmol) and the mixture wasstirred at room temperature for 5 h. Solvent was removed by rotaryevaporation. The residue was taken up in water and acidified to pH ˜1with 6N aqueous HCl, and extracted with dichloromethane. The combinedorganics were washed with brine, dried over Na₂SO₄, and concentrated tocomplete dryness to afford the desired product 33 as a white solid (1.19g, 97% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.41 (s, 9H), 1.42-1.70 (m,4H), 2.45-2.60 (m, 2H), 3.00-3.20 (m, 2H), 4.60 (s, 2H), 6.80 (d, 2H),7.08 (d, 2H). m/z (ESI): 322 [C₁₇H₂₅NO₅−H]⁻.

(4-{4-[(1H-Imidazol-2-yl-carbamoyl)methoxy]phenyl}butyl)carbamic acidtert-butyl ester (34)

[4-(4-tert-Butoxycarbonylaminobutyl)phenoxy]acetic acid 33 (1.19 g, 3.68mmol) was dissolved in anhydrous THF (10 mL), CH₂Cl₂ (10 mL) and CH₃CN(5 mL). To the solution were sequentially added HOAt (200 mg, 1.47mmol), DMAP (135 mg, 1.10 mmol), and diisopropylethylamine (3.2 mL,18.40 mmol), followed by the addition of EDC.HCl (1.03 g, 5.35 mmol).The reaction mixture was stirred at room temperature for 15 min. Aminoimidazole sulfate (583 mg, 4.41 mmol) was then added and stirring wascontinued for 48 h. Solvents were removed by rotary evaporation. Theresidue was taken up in CH₂Cl₂ (250 mL), washed with water and brine,and concentrated under reduced pressure. Flash silica gel columnchromatography eluting with methanol/dichloromethane (1:30, 1:20, v/v)gave the desired amide as a white solid (0.95 g, 66% yield). ¹H NMR (300MHz, CD₃OD) δ 1.40 (s, 9H), 1.42-1.70 (m, 4H), 2.48-2.60 (m, 2H),3.00-3.20 (m, 2H), 4.65 (s, 2H), 6.79-6.89 (m, 4H), 7.10 (d, 2H). m/z(ESI): 389 [C₂₀H₂₈N₄O₄+H]⁺.

2-[4-(4-Aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamidedihydrochloride (35)

(4-{4-[(1H-Imidazol-2-yl-carbamoyl)methoxy]phenyl}butyl)carbamic acidtert-butyl ester 34 (950 mg, 2.45 mmol) was treated with HCl (4 M indioxane, 24 mL, 96 mmol) at room temperature for 12 h. The reactionmixture was concentrated in vacuo and further co-evaporated withdichloromethane and methanol, and dried under high vacuum. The desiredproduct was obtained as a white solid (779 mg, 98%) and used directlywithout flrther purification. ¹H NMR (300 MHz, CD₃OD) δ 1.59-1.74 (m,4H), 2.55-2.67 (m, 2H), 2.85-2.98 (m, 2H), 4.80 (s, 2H), 7.00 (d, 2H),7.18 (d, 2H), 7.19 (s, 2H). m/z (ESI): 289 [C₁₅H₂₀N₄O₂+H]⁺.

2-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)acetamidedihydrochloride (36, PSA 16437)

A solution of 2-[4-(4-aminobutyl)phenoxy]-N-(1H-imidazol-2-yl)acetamidedihydrochloride 35 (99 mg, 0.27 mmol) and diisopropylethylamine (0.27mL, 1.53 mmol) in absolute ethanol (4 mL) and anhydrous methanol (3 mL)was stirred at 70° C. for 30 min, after which1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (130 mg, 0.34 mmol) was added in one portion. The reactionmixture was stirred for 3 h and then cooled to room temperature. Theyellow insolubles were removed by suction filtration and the liquidfiltrate was concentrated by rotary evaporation. The crude residue waspurified by flash silica gel column chromatography eluting withdichloromethane/methanol/concentrated ammonium hydroxide (200:10:0,200:10:1, 150:10:1, and 100:10:1, v/v) to give2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-(1H-imidazol-2-yl)-acetamideas a yellow solid (44 mg, 29% yield). The free base thus obtained wasdissolved in methanol and treated with 4 drops of 4 N aqueous HCl. Thesolution was concentrated under reduced pressure and further dried undervacuum to give the final compound 36. mp 172-174° C. ¹H NMR (300 MHz,CD₃OD) δ 1.61-1.77 (m, 4H), 2.58-2.70 (m, 2H), 3.32-3.40 (m, 2H), 4.80(s, 2H), 7.00 (d, 2H), 7.18 (d, 2H), 7.20 (s, 2H). m/z (ESI): 501[C₂₁H₂₅ClN₁₀O₃+H]⁺.

Example 9 Synthesis ofN-carbamoylmethyl-2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}phenoxy)acetamide(PSA 16314)

(4-{4-[(Carbamoylmethylcarbamoyl)methoxy]phenyl}butyl)carbamic acidbenzyl ester (37)

Compound 1 (0.50 g, 1.77 mmol) was dissolved in DMF (10 mL). To thesolution was added crushed NaOH (0.107 g, 2.66 mmol). The mixture wasstirred at room temperature for 30 min. 2-Bromoacetamide (0.367 g, 2.66mmol) was added. The reaction was further stirred at room temperatureovernight, quenched with water (2 mL) and partitioned between water anddichloromethane (each 50 mL). The organic layer was separated, washedwith water (2×50 mL), dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was purified on silica gel, eluting with a mixtureof methanol/dichloromethane (7:93, v/v), to afford the desired product37 (0.131 g, 18% yield) as a white solids. ¹H NMR (300 MHz, CDCl₃): δ1.58 (m, 4H), 2.60 (t, 2H), 3.20 (m, 2H), 4.04 (d, 2H), 4.54 (s, 2H),4.75 (br, 2H), 5.12 (s, 2H), 5.43 (br, 1H), 5.80 (br, 1H), 6.85 (d, 2H),7.12 (d, 2H), 7.36 (m, 5H). m/z (APCI): 414 [C₂₂H₂₇N₃O₅+H]⁺.

2-[4-(4-Aminobutyl)phenoxy]-N-carbamoylmethylacetamide (38)

Compound 37 (130 mg, 0.314 mmol) was dissolved in EtOH and THF (14 mL,1/1 ratio). The reaction vessel was purged with nitrogen both before andafter the catalyst (100 mg, 10% Pd/C, 50% wet) was added. The mixturewas stirred under hydrogen atmosphere (1 atm) overnight. After purgingwith nitrogen, the catalyst was vacuum filtered and washed with ethanol(3×5 mL). The combined filtrates were concentrated under vacuum. Theresidue was chromatographed on silica gel, eluting with a mixture ofconcentrated ammonium hydroxide/methanol/dichloromethane (2:20:88, v/v),to afford the desired product 38 (80 mg, 91% yield) as a white solid. ¹HNMR (300 MHz, CD₃OD): δ 1.62 (m, 4H), 2.60 (t, 2H), 2.75 (t, 2H), 3.92(s, 2H), 4.54 (s, 2H), 6.92 (d, 2H), 7.14 (d, 2H).

N-Carbamoylmethyl-2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidino]butyl}phenoxy)acetamide(39, PSA 16314)

Compound 38 (79 mg, 0.283 mmol) was dissolved in a mixture of absoluteethanol (5 mL) and Hunig's base (0.25 mL, 1.41 mmol) at 65° C. over 10min. To the solution was added1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (132 mg, 0.34 mmol) in one portion. The newly resultingreaction mixture was continuously stirred for an additional 2 h beforeit was cooled down to ambient temperature and subsequently concentratedunder vacuum. The resulting residue was purified by chromatographyeluting with methanol/dichloromethane/concentrated ammonium hydroxide(10/2/88, v/v) to afford the free base (93 mg, 67% yield) as a yellowsolid. The HCl salt was made using the following procedure: 45 mg of thefree base was suspended in ethanol (2 mL) and treated with concentratedHCl (12 N, 0.5 mL) for 10 min. All liquid was then completely removedunder vacuum to afford 39 (47 mg). mp 178-180° C. (decomposed). ¹H NMR(300 MHz, DMSO-d₆): δ 1.61 (m, 4H), 2.58 (t, 2H), 3.32 (m, 2H), 3.70 (s,2H), 4.48 (s, 2H), 6.93 (d, 2H), 7.08 (br, 1H), 7.13 (d, 2H), 7.36 (br,1H), 7.44 (br, 2H), 8.17 (t, 1H), 8.74 (br, 1H), 8.90 (br, 2H), 9.18 (t,1H), 10.48 (br, 1H). m/z (APCI): 492 [C₂₀H₂₆ClN₉O₄+H]⁺.

Example 10 Synthesis ofN-[4-(4-cyanomethoxyphenyl)butyl]-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidine(PSA 16208)

[4-(4-Cyanomethoxyphenyl)butyl]carbamic acid tert-butyl ester (40)

A mixture of [4-(4-hydroxyphenyl)butyl]carbamic acid tert-butyl ester 31(0.365 g, 1.37 mmol) and Cs₂CO₃ (0.672 g, 2.06 mmol) in anhydrous DMF (8mL) was heated at 65° C. for 30 min. Iodoacetonitrile (0.276 g, 1.651mmol) was then added to the mixture in one portion. The mixture wasstirred at 65° C. overnight, and then cooled to room temperature. Theprecipitated solid was filtered, and the filtrate was partitionedbetween water and dichloromethane (each 50 mL). The organic layer wasseparated, washed with brine (3×50 mL), dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was chromatographed on silicagel, eluting with a mixture of diethyl ether/dichloromethane (6:94,v/v), to afford the desired product 40 (0.109 g, 38% yield) as acolorless viscous oil. ¹H NMR (300 MHz, CDCl₃): δ 1.43 (s, 9H), 1.57 (m,4H), 2.60 (t, 2H), 3.15 (m, 2H), 4.49 (br, 1H), 4.75 (s, 2H), 6.91 (d,2H), 7.13 (d, 2H).

[4-(4-Aminobutyl)phenoxy]acetonitrile (41)

Compound 40 (0.105 g, 0.345 mmol) was dissolved in dichloromethane (10mL). Trifluoroacetic acid (2 mL) was added in one portion. The mixturewas stirred at room temperature for 2 h, and then concentrated undervacuum to dryness. The crude residue was used directly without furtherpurification. ¹H NMR (300 MHz, CD₃OD): δ 1.60-1.75 (m, 4H), 2.65 (t,2H), 2.92 (t, 2H), 4.38 (s, 2H), 6.96 (d, 2H), 7.20 (d, 2H). m/z (APCI):205 [C₁₂H₁₆N₂O+H]⁺.

N-[4-(4-Cyanomethoxyphenyl)butyl]-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidine(42, PSA 16208)

A mixture of compound 41 (0.070 g, 0.345 mmol) and Hunig's base (0.3 mL,1.72 mmol) in anhydrous ethanol was heated at 65° C. for 20 min. To thesolution was added1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (0.148 g, 0.379 mmol) in one portion. The heating wascontinued for another 2 h. The reaction mixture was then concentratedunder vacuum. The residue was chromatographed by flash columnchromatography and further purified by preparative TLC, eluting withmethanol/dichloromethane/concentrated ammonium hydroxide (10/1/89, v/v),to afford the desired product 42 (0.031 g, 22%) as a yellow solid. mp129-132° C. ¹H NMR (300 MHz, CD₃OD): δ 1.72 (m, 4H), 2.68 (t, 2H), 3.32(m, 2H), 4.92 (s, 2H), 6.95 (d, 2H), 7.22 (d, 2H); m/z (APCI): 417[C₁₈H₂₁ClN₈O₂+H]⁺.

Example 11 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]phenyl}butyl)guanidine(PSA 15143)

(4-{4-[3-(2,3-Dihydroxypropoxy)-2-hydroxypropoxy]phenyl}butyl)carbamicacid benzyl ester (43)

A solution containing compound 1 (2.0 g, 6.68 mmol), triethylamine(0.093 mL, 0.668 mmol) and anhydrous ethanol (2.2 mL) was heated at 70°C. for 1 h. Oxiranylmethanol (0.5 mL, 6.68 mmol) was added every hourfor a total of 4 h (the total amount of oxiranylmethanol added was 2.0ml, 26.72 mmol). The reaction was concentrated under vacuum. The residuewas chromatographed on silica gel with the elution of a mixture ofmethanol/dichloromethane (3:97, v/v) to provide 168 mg (4.6% yield) ofthe desired product 43. m/z (APCI): 448 [C₂₄H₃₃NO₇+H]⁺.

3-{3-[4-(4-Aminobutylphenoxy]-2-hydroxypropoxy}propane-1,2-diol (44)

A solution containing the compound 43 (0.15 g, 0.34 mmol) in ethanol(1.5 mL) was purged with nitrogen before and after the catalyst (0.15 g,10% Pd/C, 50% wet) was added. The reaction mixture was placed underhydrogenation atmosphere for 45 min. The catalyst was vacuum filteredthrough diatomaceous earth and washed with ethanol (3×2 mL). Thecombined filtrates were concentrated under vacuum. The residue waschromatographed on silica gel, eluting withmethanol/dichloromethane/concentrated ammonium (25/2.5/73.5, v/v), toafford the desired product 44 (0.053 g, 51% yield) as a colorless,viscous oil. ¹H NMR (300 MHz, CD₃OD): δ 1.52 (m, 4H), 2.55 (t, 2H), 2.65(t, 2H), 3.61 (m, 10H), 6.85 (d, 2H), 7.09 (d, 2H). m/z (APCI): 314[C₁₆H₂₇NO₅+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-(4-{4-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]phenyl}butyl)guanidine(45, PSA 15143)

Compound 44 (50 mg, 0.159 mmol) was dissolved in a mixture of absoluteethanol (0.5 mL) and triethylamine (0.076 mL, 0.541 mmol) at 65° C. over15 min. To the solution was added1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (74 mg, 0.191 mmol). The reaction mixture was stirred at theabove temperature for an additional 50 min, cooled down to ambienttemperature and subsequently concentrated under vacuum. The residue waschromatographed on silica gel, eluting withmethanol/dichloromethane/concentrated ammonium hydroxide (10/1/40, v/v)to afford the desired product 45 (53 mg, 36% yield) as a yellow solid.mp 73-82° C. (decomposed). ¹H NMR (300 MHz, CD₃OD): δ 1.70 (m, 4H), 2.55(m, 2H), 3.22 (m, 2H), 3.65 (m, 7H), 3.98 (m, 3H), 6.86 (d, 2H), 7.08(d, 2H). m/z (APCI): 526 [C₂₂H₃₂ClN₇O₆+H]⁺.

Example 12

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (DMSO-d₆) Melting Point 108-110° C.dec HPLC Analysis 96.5% (area percent), Polarity dC18 Column, Detector @220 nm Miscellaneous Tests: m/z 527 [C₂₁H₃₁ClN₈O₄S + H]⁺ ESI MassSpectrum

Example 13

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (DMSO-d₆) Melting Point 153-155° C.dec HPLC Analysis 96.3% (area percent), Polarity dC18 Column, Detector @220 nm Miscellaneous Tests: m/z 465 [C₁₉H₂₅ClN₈O₂S + H]⁺ ESI MassSpectrum

Example 14

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 500 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 115-116° C. decHPLC Analysis 97.1% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 639 [C₃₀H₃₅ClN₈O₆ + H]⁺ ESI Mass Spectrum

Example 15

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 190-192° C. decHPLC Analysis 97.9% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 476 [C₂₀H₂₆ClN₉O₃ + H]⁺ ESI Mass Spectrum

Example 16

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 124-126° C. decHPLC Analysis 95.2% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 441 [C₁₆H₂₁ClN₈O₃S + H]⁺ ESI Mass Spectrum

Example 17

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 500 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 189° C. decHPLC Analysis 95.0% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 503 [C₂₁H₂₇ClN₁₀O₃ + H]⁺ ESI Mass Spectrum

Example 18

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Pale yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 195-197° C. decHPLC Analysis 97.4% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 477 [C₂₀H₂₅ClN₈O₄ + H]⁺ ESI Mass Spectrum

Example 19

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Melting Point 210-212° C. decHPLC Analysis 95.5% (area percent), Polarity dC18 Column, Detector @ 220nm Miscellaneous Tests: m/z 486 [C₂₂H₂₈ClN₉O₂ + H]⁺ ESI Mass Spectrum

Example 20

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Optical Rotation [α]²⁵ _(D) −7.8° (c 0.30, Methanol) Melting Point 178-180° C. dec HPLC Analysis97.0% (area percent), Polarity dC18 Column, Detector @ 220 nmMiscellaneous Tests: m/z 490 [C₂₁H₂₈ClN₉O₃ + H]⁺ ESI Mass Spectrum

Example 21

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Optical Rotation [α]²⁵ _(D) +0.5° (c 0.35, Methanol) Melting Point 215° C. dec HPLC Analysis 96.1%(area percent), Polarity dC18 Column, Detector @ 220 nm MiscellaneousTests: m/z 462 [C₂₀H₂₈ClN₉O₂ + H]⁺ ESI Mass Spectrum

Example 22

Utilizing the procedures set forth above, the following CappedPyrazinoylguanidine was prepared.

TEST RESULT/REFERENCE Description Yellow solid Identification:Consistent 300 MHz ¹H NMR Spectrum (CD₃OD) Optical Rotation [α]²⁵ _(D) +4.1+ (c 0.30, Methanol) Melting Point 230° C. dec HPLC Analysis 95.3%(area percent), Polarity dC18 Column, Detector @220 nm MiscellaneousTests: m/z 463 [C₂₀H₂₇ClN₈O₃ + H]⁺ ESI Mass Spectrum

Example 23

Sodium Channel Blocking Activity of Selected CappedPyrazinoylguanidines. Fold Amiloride** PSA EC₅₀(nM) (PSA 4022 = 100)15143 7 ± 3 (n = 3) 107 ± 11 (n = 3) 16208 11 ± 4 (n = 6) 52 ± 21 (n =6) 16314 13 ± 2 (n = 4) 41 ± 6 (n = 4) 16313 15 ± 4 (n = 4) 41 ± 7 (n =4) 16437 13 ± 7 (n = 7) 77 ± 53 (n = 7) 17482 16 ± 4 (n = 3) 39 ± 6 (n =3) 17846 11 ± 6 (n = 4) 104 ± 49 (n = 4) 17926 25 ± 9 (n = 6) 29 ± 12 (n= 6) 17927 13 ± 4 (n = 3) 83 ± 26 (n = 3) 18211 10 ± 4 (n = 3) 112 ± 52(n = 2) 18212 27 ± 17 (n = 4) 32 ± 16 (n = 4) 18229 15 ± 6 (n = 3) 49 ±15 (n = 3) 18361 11 ± 4 (n = 3) 76 ± 25 (n = 3) 18592 8 ± 4 (n = 2) 136± 58 (n = 2) 18593 48 ± 16 (n = 6) 13 ± 4 (n = 4) 19007 18 ± 13 (n = 4)42 ± 17 (n = 4) 19008 9 ± 1 (n = 4) 54 ± 6 (n = 4) 19912 26 ± 8 (n = 4)32 ± 10 (n = 4) 23022 12 ± 3 (n = 4) 79 ± 15 (n = 4) 24406 8 ± 3 (n = 6)107 ± 38 (n = 6) 24407 32 ± 11 (n = 10) 23 ± 4 (n = 10) 24851 28 ± 13 (n= 8) 25 ± 10 (n = 8)**Relative potency for PSA 4022 = 100 using EC₅₀ from PSA 4022 in samerun

The following examples depict the synthesis of compounds according toFormula II.

FORMULA II EXAMPLES

General Procedures

Method A. Mono-Protection of Symmetrical Diamine by Boc-Protecting Group

The diamine was dissolved in anhydrous methanol. To the solution wasadded Hunig's base (DIPEA, 3 equiv). The newly resulting solution wasstirred at room temperature for 30 min. To the reaction mixture wasslowly added (over 2 to 4 hours) a solution of Boc₂O (1 equiv) dissolvedin anhydrous methanol. After the addition, the reaction mixture wasstirred for an additional 2 hours, then quenched with water. The productwas extracted with dichloromethane. The combined extracts were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas chromatographed on silica gel eluting with a mixture of methanol anddichloromethane. The fractions containing the desired product werecollected and concentrated under vacuum. The product wasspectroscopically characterized.

Method B. Removal of Boc-Protecting Group from Amino or Guanidino Group

The compound containing Boc-protected amino or guanidino group wasdissolved in methanol. The solution was then treated with concentratedHCl (12 N) at room temperature for 1 to 2 hours. All liquid in thereaction mixture was then completely removed under vacuum. The resultingresidue was further dried under vacuum and generally directly used inthe next step without purification.

Method C. Guanylation of Free Amine by Reaction with(tert-butoxycarbonylamino-trifluoromethanesulfonyliminomethyl)carbamicacid tert-butyl ester (Goodman's Reagent)

To a solution containing the free amine dissolved in anhydrous methanolwas added Hunig's base (DIPEA, 3 equiv). The newly resulting solutionwas stirred at room temperature for 30 min before the Goodman's reagentwas added (1.5 equiv). The stirring was continued for an additional 3 to5 hours. The reaction mixture was concentrated. The resulting residuewas chromatographed on silica gel eluting with a mixture ofdichloromethane, methanol, and concentrated ammonium hydroxide (CMA).The fractions containing the desired product were collected andconcentrated. The product was characterized by spectroscopic methods.

Method D. Coupling of Un-Protected Amine with1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (Cragoe Compound)

The un-protected amine was dissolved in anhydrous ethanol. To thesolution was added Hunig's base (DIPEA, 3 equiv). The newly resultingsolution was heated at 65° C. for 15 min. The Cragoe compound (1.2equiv) was then added. The reaction mixture was stirred at 65° C. for anadditional 2 to 3 hours, and then cooled to room temperature before itwas concentrated under vacuum. The resulting residue was chromatographedon silica gel eluting with CMA. The appropriate fractions were collectedand concentrated under vacuum. The desired product (typically a yellowsolid) was characterized by spectroscopic methods.

Example 1 Synthesis ofN-(6-aminohexyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinedihydrochloride (PSA 18706)

{6-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]hexyl}carbamicacid tert-butyl ester (2a)

Compound 2a was synthesized from 1a, 6-aminohexylcarbamic acidtert-butyl ester (Scheme 1), in 90% yield using method D. ¹H NMR (300MHz, CD₃OD): δ 1.42 (s, 9H), 1.46-1.65 (m, 8H), 3.04 (t, 2H), 3.22 (t,2H). m/z (APCI): 429 [C₁₇H₂₉ClN₈O₃+H]⁺.

N-(6-Aminohexyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinedihydrochloride (3a, PSA 18706)

Compound 3a was synthesized from compound 2a in 34% yield using methodB. mp>240° C. ¹H NMR (300 MHz, CD₃OD): δ 1.42-1.54 (m, 4H), 1.65-1.78(m, 4H), 2.94 (t, 2H), 3.34 (t, 2H). m/z (APCI): 329 [C₁₂H₂₁ClN₈O+H]⁺.

Example 2 Synthesis ofN-(7-aminoheptyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidine(PSA 18705)

Compound 3b (PSA 18705) was synthesized from heptane-1,7-diamine in 65%yield using method D. mp 185-187° C. (decomposed). ¹H NMR (300 MHZ,CD₃OD): δ 1.40-1.55 (m, 6H), 1.58-1.76 (m, 4H), 2.80 (t, 2H), 3.30 (m,2H). m/z (ESI): 343 [C₁₃H₂₃ClN₈O+H]⁺.

Example 3 Synthesis ofN-{7-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]heptyl}guanidinedihydrochloride (PSA 19155)

N-(7-Aminoheptyl)-[N′,N′-bis-(tert-butoxycarbonyl)]guanidine (6b)

Compound 6b was synthesized from heptane-1,7-diamine (Scheme 2) in 43%yield using method C. ¹H NMR (300 MHz, CDCl₃): δ 1.44-1.50 (m, 10H),1.55 (s, 18H), 1.84 (t, 2H), 2.78 (t, 2H), 3.46 (t, 2H). m/z (ESI): 373[C₁₈H₃₆N₄O₄+H]⁺.

N-{7-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]heptyl}guanidinedihydrochloride (5b, PSA 19155)

Compound 6b was reacted with the Cragoe compound according to method D(Scheme 2). The product of the reaction, after chromatographicpurification, was directly treated with concentrated HCl using method Bto afford the desired compound 5b in 17% overall yield. mp 140-142° C.¹H NMR (300 MHz, CD₃OD): δ 1.42-1.54 (m, 6H), 1.60-1.82 (m, 4H), 3.18(t, 2H), 3.34 (m, 2H). m/z (ESI): 385 [C₁₄H₂₅ClN₁₀O+H]⁺.

Example 4 Synthesis of{8-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]octyl}carbamicacid tert-butyl ester (PSA 19156)

Octane-1,8-diamine was mono-protected by Boc-protecting group usingmethod A (Scheme 1). The product from this step was directly reactedwith the Cragoe compound using method D, which afforded the desiredproduct 2c (PSA 19156) in 81% yield. mp 189-191° C. ¹H NMR (300 MHz,CD₃OD): δ 1.38-1.56 (m, 19H), 1.70 (m, 2H), 3.02 (t, 2H), 3.24 (t, 2H).m/z (ESI): 457 [C₁₉H₃₃ClN₈O₃+H]⁺.

Example 5 Synthesis ofN-(8-aminooctyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidinedihydrochloride (PSA 19336)

Compound 3c (PSA 19336) was synthesized from 2c using method B. mp253-255° C. ¹H NMR (300 MHz, CD₃OD) 6 1.40 (m, 8H), 1.66 (m, 4H), 2.90(m, 2H), 3.32 (m, 2H). m/z (ESI): 357 [C₁₄H₂₅ClN₈O+H]⁺.

Example 6 Synthesis ofN-{8-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]octyl}{N″,N′″-bis-(tert-butoxycarbonyl)}guanidine(PSA 19486)

Compound 4c (PSA 19486) was synthesized from 3c in 52% yield usingmethod C. mp 208-210° C. (decomposed). ¹H NMR (300 MHz, CD₃OD) δ1.33-1.72 (m, 30H), 3.18-3.39 (m, 4H). m/z (ESI): 599[C₂₅H₄₃ClN₁₀O₅+H]⁺.

Example 7 Synthesis ofN-{8-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]octyl}-guanidinedihydrochloride (PSA 19604)

Compound 5c (PSA 19604) was synthesized from 4c in quantitative yieldusing method B. mp 130-132° C. ¹H NMR (300 MHz, CD₃OD) δ 1.33-1.72 (m,12H), 3.18-3.39 (m, 4H). m/z (ESI): 399 [C₁₅H₂₇ClN₁₀O+H]⁺.

Example 8 Synthesis of{9-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]nonyl}-carbamicacid tert-butyl ester (PSA 19484)

Compound 2d (PSA 19484) was synthesized in a similar method to compound2c (PSA 19156). mp 187-189° C. ¹H NMR (500 MHz, CD₃OD) δ 1.35 (m, 12H),1.41 (s, 9H), 1.60 (m, 2H), 3.00 (m, 2H), 3.20 (m, 2H). m/z (ESI): 471[C₂₀H₃₅ClN₈O₃+H]⁺.

Example 9 Synthesis ofN-(9-aminononyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidinedihydrochloride (PSA 19335)

Compound 3d (PSA 19335) was synthesized in quantitative yield from 2d(PSA 19484) using method B. mp 155-157° C. (decomposed). ¹H NMR (300MHz, CD₃OD) δ 1.40 (m, 10H), 1.70 (m, 4H), 2.90 (m, 2H), 3.32 (m, 2H).m/z (ESI): 357 [C₁₅H₂₇ClN₈O+H]⁺.

Example 11 Synthesis ofN-{9-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]nonyl}guanidinedihydrochloride (PSA 19006)

Compound 5d (PSA 19006) was synthesized similarly to compound 5c (PSA19155). mp 178-180° C. ¹H NMR (300 MHz, CD₃OD): δ 1.44-1.54 (m, 10H),1.58-1.80 (m, 4H), 3.20 (t, 2H), 3.34 (m, 2H). m/z (ESI): 413[C₁₆H₂₉ClN₁₀O+H]⁺.

Example 12 Synthesis of{10-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]decyl}-carbamicacid tert-butyl ester (PSA 19485)

Compound 2e (PSA 19485) was synthesized in a similar method to compound2c. mp 186-188° C. ¹H NMR (300 MHz, CD₃OD) δ 1.29-1.51 (m, 23H),1.59-1.70 (m, 2H), 3.02 (t, 2H), 3.19-3.28 (m, 2H). m/z (ESI): 485[C₂₁H₃₇ClN₈O₃+H]⁺.

Example 13 Synthesis ofN-(10-aminodecyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidinedihydrochloride (PSA 19487)

Compound 3e (PSA 19487) was synthesized from compound 2e using method B.mp 168-170° C. ¹H NMR (300 MHz, CD₃OD) δ 1.41(m, 12H), 1.57-1.79 (m,4H), 2.84-2.99 (m, 2H), 3.34-3.40 (m, 2H); m/z (ESI): 385[C₁₆H₂₉ClN₈O+H]⁺.

Example 14 Synthesis ofN-{10-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-decyl}guanidinedihydrochloride (PSA 23608)

Compound 3e (PSA 19487) was reacted with the Goodman's reagent(Scheme 1) according to method C. The product of the reaction, afterchromatographic purification, was directly treated with concentrated HClusing method B to afford the desired product 5e (PSA 23608). mp 156-158°C. ¹H NMR (500 MHz, CD₃OD) δ 1.31-1.48 (m, 12H), 1.55-1.62 (m, 2H),1.65-1.76 (m, 2H), 3.11-3.19 (m, 2H), 3.34-3.38 (m, 2H). m/z (ESI): 427[C₁₇H₃₁ClN₁₀O+H]⁺.

Example 15 Synthesis of{11-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]undecyl}carbamicacid tert-butyl ester (PSA 23777)

Compound 2f (PSA 23777) was synthesized in a similar method to compound2c (PSA 19156). mp 82-84° C. ¹H NMR (500 MHz, CD₃OD) δ 1.27 (s, 12H),1.45 (s, 13H), 1.65 (m, 2), 2.95 (m, 2H), 3.21 (m, 2H). m/z (APCI): 499[C₂₂H₃₉ClN₈O₃+H]⁺.

Example 16 Synthesis ofN-(11-aminoundecyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinedihydrochloride (PSA 23682)

Compound 3f (PSA 23682) was synthesized from 2f using method B. mp220-222° C. ¹H NMR (500 MHz, CD₃OD) δ 1.35 (m, 14H), 1.65 (m, 4H), 2.91(m, 2H), 3.31 (m, 2H). m/z (APCI): 399 [C₁₇H₃₁ClN₈O+H]⁺.

Example 17 Synthesis ofN-{11-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]-undecyl}guanidinedihydrochloride (PSA 23991)

Compound 5f (PSA 23991) was synthesized in a similar manner to compound5e. mp 151-153° C. ¹H NMR (300 MHz, DMSO-d₆) δ 1.27 (m, 18H), 1.45 (m,2H), 1.55 (m, 2H), 3.07 (m, 2H), 3.27 (m, 2H), 7.43 (m, 2H), 7.66 (m,1H), 8.78 (br, 1H), 8.94(br, 1H), 9.25 (br, 1H), 10.5 (br, 1H). m/z(APCI): 441 [C₁₈H₃₃ClN₁₀O+H]⁺.

Example 18 Synthesis of{12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecyl}-carbamicacid tert-butyl ester (PSA 23776)

Compound 2g (PSA 23776) was synthesized similarly to compound 2c. mp154-156° C. ¹H NMR (500 MHz, CD₃OD) δ 1.25 (m, 14H), 1.47 (m, 13H), 1.65(m, 2H), 2.98 (m, 2H), 3.21 (m, 2H). m/z (APCI): 513 [C₂₃H₄₁ClN₈O₃+H]⁺.

Example 19 Synthesis ofN-(12-aminododecyl)-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)-guanidinedihydrochloride (PSA 23609)

Compound 3g (PSA 23609) was synthesized from compound 2g using method B.mp 235-237° C. ¹H NMR (500 MHz, CD₃OD) δ 1.35 (m, 16H), 1.65 (m, 4H),2.89 (m, 2H), 3.31 (m, 2H). m/z (ESI): 413 [C₁₈H₃₃ClN₈O+H]⁺.

Example 20 Synthesis ofN-{12-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]dodecyl)guanidinedihydrochloride (PSA 23683)

Compound 5g (PSA 23683) was synthesized from compound 3g in a similarmethod to 5b. mp 145-147° C. ¹H NMR (500 MHz, CD₃OD) δ 1.30-1.48 (m,16H), 1.64 (t, 2H), 1.75 (t, 2H), 3.18 (t, 2H), 3.35 (m, 2H). m/z(APCI): 455 [C₁₉H₃₅ClN₁₀O+H]⁺.

Example 21 Synthesis of(3-{3-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]propoxy}propyl])carbamicacid tert-butyl ester (PSA19333)

[3-(3-Aminopropoxy)propyl]carbamic acid tert-butyl ester (7) Compound 7was synthesized from 3-(3-aminopropoxy)propylamine (Scheme 3) usingmethod A. ¹H NMR (300 MHz, CDCl₃) δ 1.40 (m, 2H), 1.44 (s, 9H), 1.74 (m,4H), 2.81 (m, 2H), 3.23 (m, 2H), 3.48 (m, 4H), 5.03 (br s, 1H).(3-{3-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]propoxy}propyl)-carbamicacid tert-butyl ester (8, PSA 19333)

Compound 8 was synthesized from compound 7 using method D. mp 62-65° C.(decomposed). ¹H NMR (300 MHz, CD₃OD) δ 1.40 (s, 9H), 1.80 (m, 4H), 3.12(m, 2H), 3.32 (m, 2H), 3.52 (m, 4H). m/z (ESI): 445 [C₁₇H₂₉ClN₈O₄+H]⁺.

Example 22 Synthesis ofN-[3-(3-aminopropoxy)propyl]-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinedihydrochloride (PSA19157)

Compound 9 (PSA 19157) was synthesized from compound 8 (PSA 19333) usingmethod B. mp 164-166° C. (decomposed). ¹H NMR (300 MHz, CD₃OD) δ 1.95(m, 4H), 3.05 (m, 2H), 3.48 (m, 2H), 3.60 (m, 4H). m/z (ESI): 345[C₁₂H₂₁ClN₈O₂+H]⁺.

Example 23 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-[3-(3-{N″,N′″-bis-(tert-butoxycarbonyl)guanidino}propoxy)propyl]guanidine(PSA 19488)

Compound 10 (PSA 19488) was synthesized from compound 9 (PSA 19157)using method C. mp 89-93° C. ¹H NMR (300 MHz, CD₃OD) δ 1.46 (s, 9H),1.50 (s, 9H), 1.90 (m, 4H), 3.40 (m, 4H), 3.55 (m, 4H). m/z (ESI): 587[C₂₃H₃₉ClN₁₀O₆+H]⁺.

Example 24 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-[3-(3-guanidino-propoxy)propyl]guanidinedihydrochloride (PSA 19334)

Compound 11 (PSA 19334) was synthesized from compound 10 (PSA 19488)using method B. mp 72-75° C. (decomposed). ¹H NMR (300 MHz, CD₃OD) δ1.91 (m, 4H), 3.30 (m, 2H), 3.50 (m, 2H), 3.60 (m, 4H). m/z (ESI): 387[C₁₃H₂₃ClN₁₀O₂+H]⁺.

Example 25 Synthesis ofN-{2-[2-(2-aminoethoxy)ethoxy]ethyl}-N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidine(PSA 18848)

Compound 12 (PSA 18848) was synthesized from2-[2-(2-aminoethoxy)ethoxy]-ethylamine (Scheme 4) in 86% yield usingmethod D. mp 87-90° C. ¹H NMR (300 MHz, CD₃OD): δ 2.84 (t, 2H), 3.45 (t,2H), 3.54-3.66 (m, 8H). m/z (APCI): 361 [C₁₂H₂₁ClN₈O₃+H]⁺.

Example 26 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-{2-[2-(2-guanidinoethoxy)ethoxy]ethyl}guanidinedihydrochloride (PSA 18849)

Compound 14 (PSA 18849) was synthesized from compound 12 by a similarmethod used to prepared compound 5e. mp 108-112° C. (decomposed). ¹H NMR(300 MHz, CD₃OD): δ 1.38 (t, 2H), 3.38 (t, 2H), 3.57 (t, 2H), 3.67 (t,2H), 3.75 (m, 4H). m/z (APCI): 403 [C₁₃H₂₃ClN₁₀O₃+H]⁺.

Example 27

Sodium Channel Blocking Activity of Selected AlaphaticPyrazinoylguanidines. Fold Amiloride** PSA EC₅₀(nM) (PSA 4022 = 100)18705 99 ± 31 (n = 4) 8 ± 2 (n = 4) 18706 254 ± 118 (n = 4) 4 ± 1 (n =4) 19006 60 ± 15 (n = 3) 11 ± 2 (n = 3) 19155 81 ± 45 (n = 3) 8 ± 7 (n =3) 19156 46 ± 20 (n = 2) 18 ± 2 (n = 2) 19333 81 ± 8 (n = 4) 7 ± 2 (n =4) 19335 36 ± 7 (n = 4) 19 ± 7 (n = 4) 19336 76 ± 18 (n = 4) 12 ± 3 (n =3) 19484 66 (n = 1) 12 (n = 1) 19487 25 ± 11 (n = 4) 37 ± 1 (n = 4)19604 25 ± 27 (n = 4) 63 ± 61 (n = 4) 23608 17 ± 8 (n = 2) 41 ± 29 (n =2) 23609 13 ± 7 (n = 4) 66 ± 36 (n = 4) 23682 12 ± 3 (n = 3) 51 ± 15 (n= 3) 23683 41 ± 68 (n = 6) 68 ± 48 (n = 6) 23776 75 (n = 1) 7 (n = 1)23991 64 ± 77 (n = 4) 20 ± 12 (n = 4)**Relative potency for PSA 4022 = 100 using EC₅₀ from PSA 4022 in samerun

The following examples depict the synthesis of compounds according toFormula III.

FORMULA III EXAMPLES

Example 1 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(2-hydroxyethyl)piperidin-4-yl]butyl}guanidinedihydrochloride (PSA 25193)

4-(Piperidin-4-yl)butyric acid methyl ester (2)

A solution of 1 (2.00 g, 9.50 mmol) and chlorotrimethylsilane (2.30 g,20.1 mmol) in methanol (30 mL) was stirred at room temperature overnight(Scheme 1). After that, the solvent was removed under reduced pressureand the residue was purified by Flash™ chromatography (BIOTAGE, Inc)(9:1 dichloromethane/methanol, v/v) to provide 2 (1.73 g, 98%) as alight yellow solid.

¹H NMR (300 MHz, CD₃OD) δ 1.39 (m, 4H), 1.66 (m, 3H), 1.95 (d, 2H), 2.39(m, 2H), 3.02 (m, 2H), 3.40 (m, 2H), 3.69 (s, 3H). m/z (ESI): 186[C₁₀H₁₉NO₂+H]⁺.

4-[1-(2-Benzyloxyethyl)piperidin-4-yl]butyric acid methyl ester (3a)

A solution of 2 (2.00 g, 10.8 mmol), (2-bromoethoxymethyl)benzene (2.31g, 10.8 mmol), and triethylamine (4.5 ml, 32.4 mmol) in dichloromethane(30 mL) was stirred at room temperature overnight. Solvent wasevaporated and the residue was purified by Flash™ chromatography(BIOTAGE, Inc) (9.3:0.7 dichloromethane/methanol, v/v) to provide 3a(1.3 g, 42%) as a yellow oil. ¹H NMR (300 MHz, CD₃OD) δ 1.30 (m, 5H),1.66 (m, 2H), 1.87 (d, 2H), 2.37 (m, 2H), 2.58 (m, 2H), 3.04 (m, 2H),3.39 (m, 2H), 3.65 (s, 3H), 3.80 (m, 2H), 4.55 (s, 2H), 7.37 (m, 5H).m/z (ESI): 320 [C₁₉H₂₉NO₃+H]⁺.

4-[1-(2-Benzyloxyethyl)piperidin-4-yl]butyramide (4a)

Compound 3a (1.30 g, 4.0 mmol) was dissolved in 7 N NH₃ in methanol (25mL) in a sealed tube. The resulting solution was stirred at 50° C. for 3days. After that the solvent was removed under vacuum and the residuewas purified by Flash™ chromatography (BIOTAGE, Inc) (9.5:0.45:0.05dichloromethane/methanol/concentrated ammonium hydroxide, v/v) toprovide 4a (0.93 g, 78%) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ1.27 (m, 5H), 1.65 (m, 4H), 2.11 (m, 4H), 2.65 (m, 2H), 2.96 (d, 2H),3.62 (m, 2H), 4.51 (s, 2H), 7.37 (m, 5H). m/z (ESI): 305[C₁₈H₂₈N₂O₂+H]⁺.

4-[1-(2-Benzyloxyethyl)piperidin-4-yl]butylamine (5a)

To a solution of BH₃.THF (2.2 mL, 2.2 mmol) cooled to 0° C. was addedcompound 4a (100 mg, 0.3 mmol). The resulting mixture was stirred for 30min, then warmed to room temperature and stirred overnight. The reactionwas quenched with water, and extracted with Et₂O. The organic solutionwas dried over Na₂SO₄ and concentrated under vacuum to provide 5a (85.2mg, 89%) which was used directly without further purification. ¹H NMR(500 MHz, CD₃OD) δ 1.39 (m, 2H), 1.45 (m, 4H), 1.62 (m, 1H), 1.71 (m,2H), 1.95 (m, 2H), 2.87 (m, 2H), 2.97 (m, 2H), 3.25 (m, 2H), 3.45 (d,2H), 3.82 (m, 2H), 4.61 (s, 2H), 7.39 (m, 5H). m/z (ESI): 291[C₁₈H₃₀N₂O+H]⁺.

2-[4-(4-Aminobutyl)piperidin-1-yl]ethanol (6a)

A suspension of 5a (0.3 g, 1.03 mmol) and catalyst (10% palladium oncarbon, 0.8 g, 50% wet) in methanol (25 mL) was placed in a Parr shakerbottle. The system was vacuumed and flushed with nitrogen. The procedurewas repeated three times. The mixture was then shaken at roomtemperature overnight under 40 psi hydrogen atmosphere. The system wasthen vacuumed again and flushed with nitrogen. The procedure wasrepeated three times. The catalyst was filtered under vacuum and washedwith methanol (2×10 mL). The filtrate and washings were combined andconcentrated under reduced pressure to provide 6a (186 mg, 90%). Thecrude product was used directly without purification. m/z (ESI): 201[C₁₁H₂₄N₂O+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′{4-[1-(2-hydroxyethyl)piperidin-4-yl]butyl}guanidinedihydrochloride (7a, PSA 25193)

1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothioureahydriodide (290 mg, 0.73 mmol) was added to a solution of compound 6a(130 mg, 0.65 mmol) and DIPEA (0.34 mL, 1.95 mmol) in ethanol (5 mL).The reaction mixture was stirred at 65° C. for 5 h. Solvent was removedunder reduced pressure and the residue was purified by semi-preparativeHPLC (water/acetonitrile/0.1% TFA). The purified product was dissolvedin 5% HCl aqueous solution and stirred at room temperature for 30 min.The mixture was then concentrated and further dried under high vacuum toprovide 7a (15 mg, 6%) as a light yellow solid. ¹H NMR (500 MHz, CD₃OD)δ 1.50 (m, 9H), 2.01 (d, 2H), 3.05 (m, 2H), 3.20 (m, 2H), 3.61 (m, 2H),3.89 (s, 2H). m/z (ESI): 413 [C₁₇H₂₉ClN₈O₂+H]⁺. mp 168-170° C.

Example 2 Synthesis ofN-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(3-hydroxypropyl)piperidin-4-yl]butyl}guanidinedihydrochloride (PSA 25310)

4-[1-(3-Benzyloxypropyl)piperidin-4-yl]butyric acid methyl ester (3b)

Following the same procedure described for the preparation of compound3a, the compound 3b was synthesized in 40% yield from compound 2 as ayellow oil.

¹H NMR (300 MHz, CD₃OD) δ 1.21 (m, 4H), 1.42 (m, 1H), 1.49 (m, 2H), 1.83(d, 2H), 1.93 (m, 2H), 2.31 (m, 2H), 2.69 (m, 2H), 2.99 (m, 2H), 3.35(m, 2H), 3.60 (m, 5H), 4.50 (m, 2H), 7.28 (m, 5H). m/z (ESI): 334[C₂₀H₃₁NO₃+H]⁺.

4-[1-(3-Benzyloxypropyl)piperidin-4-yl]butyramide (4b)

Following the same procedure described for the preparation of compound4a, compound 4b was synthesized in 69% yield from compound 3b as ayellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ 1.25 (m, 5H), 1.49 (m, 2H), 1.68 (m, 2H),1.85 (m, 2H), 2.01 (m, 2H), 2.40 (m, 2H), 2.75 (m, 2H), 3.13 (m, 3H),3.45 (m, 3H), 4.47 (m, 2H), 7.37 (m, 5H). m/z (ESI): 319[C₁₉H₃₀N₂O₂+H]⁺.

4-[1-(3-Benzyloxypropyl)piperidin-4-yl]butylamine (5b)

Following the same procedure described for the preparation of compound5a, compound 5b was synthesized in 70% yield from compound 4b as a lightyellow solid. ¹H NMR (500 MHz, CDCl₃) δ 1.16 (m, 5H), 1.29 (m, 2H), 1.43(m, 2H), 1.61 (m, 3H), 1.85 (m, 5H), 2.60 (m, 3H), 2.70 (m, 1H), 2.95(m, 2H), 3.50 (m, 2H), 4.51 (s, 2H), 7.39 (m, 5H). m/z (ESI): 305[C₁₉H₃₂N₂O+H]⁺.

3-[4-(4-Aminobutyl)piperidin-1-yl]propan-1-ol (6b)

Following the same procedure described for the preparation of compound6a, compound 6b was synthesized in 90% yield from compound 5b as a lightyellow solid. ¹H NMR (500 MHz, CDCl₃) δ 1.20 (m, 7H), 1.41 (m, 2H), 1.65(m, 5H), 1.89 (m, 2H), 2.60 (m, 4H), 3.00 (m, 4H), 3.79 (m, 2H). m/z(ESI): 215 [C₁₂H₂₆N₂O+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(3-hydroxypropyl)piperidin-4-yl]butyl}guanidinedihydrochloride (7b, PSA 25310)

Following the same procedure described for the preparation of compound7a, compound 7b was synthesized in 40% yield from compound 6b as ayellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ 1.25 (m, 5H), 1.52 (m, 5H), 1.85 (m, 4H),2.85 (m, 2H), 3.00 (m, 2H), 3.15 (m, 1H), 3.31 (m, 2H), 3.45 (m, 4H),7.41 (m, 3H), 8.90 (m, 2H), 9.40 (m, 1H). m/z (ESI): 427[C₁₈H₃₁ClN₈O₂+H]⁺. mp 165-167° C.

Example 3 Synthesis ofN-{4-[1-(2-aminoethyl)piperidin-4-yl]butyl}-N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidinetrihydrochloride (PSA 25455)

4-[1-(2-tert-Butoxycarbonylaminoethyl)piperidin-4-yl]butyric acid methylester (3c)

Following the same procedure described for the preparation of compound3a, compound 3c was synthesized from compound 2 as an off white solid.¹H NMR (300 MHz, CD₃OD) δ 1.18-1.35 (m, 7H), 1.41 (m, 9H), 1.59-1.84 (m,5H), 2.29-2.37 (m, 2H), 2.41-2.52 (m, 2H), 2.86-3.02 (m, 2H), 3.13-3.24(m, 2H), 3.67 (s, 3H). m/z (ESI): 329 [C₁₇H₃₂N₂O₄+H]⁺.

{2-[4-(3-Carbamoylpropyl)piperidin-1-yl]ethyl}carbamic acid tert-butylester (4c)

Following the same procedure described for the preparation of compound4a, compound 4c was synthesized from compound 3c as an off-white solid.¹H NMR (300 MHz, CD₃OD) δ 1.18-1.35 (m, 7H), 1.41 (m, 9H), 1.59-1.84 (m,5H), 2.29-2.37 (m, 2H), 2.41-2.52 (m, 2H), 2.86-3.02 (m, 2H), 3.13-3.24(m, 2H). m/z (ESI): 314 [C₁₆H₃₁N₃O₃+H]⁺.

{2-[4-(4-Aminobutyl)piperidin-1-yl]ethyl}carbamic acid tert-butyl ester(5c)

A solution of compound 4c (250 mg, 0.80 mmol) in dichloromethane (10 mL)was cooled to 0° C., then DIBA1-H (7.4 mL, 7.4 mmol of 1M in toluene)was added dropwise into the solution over 45 min. The mixture wasstirred for 1 hour, then warmed to room temperature and stirred for 14h. The reaction was quenched with potassium sodium tartrate aqueoussolution. The mixture was extracted with dichloromethane (3×10 mL). Thecombined extracts were washed with water and brine, dried over sodiumsulfate and concentrated under vacuum to afford an oil. Purification bycolumn chromatography (silica; 90:10, v/v, dichloromethane/methanolfollowed by 89:10:1 dichloromethane/methanol/ammonium hydroxide)produced the desired product 5c (54 mg, 23% un-optimized yield) as aclear colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 1.21-1.26 (m, 8H),1.42-1.46 (m, 11H), 1.641.67 (m, 3H), 1.91-1.99 (m, 2H), 2.41-2.48 (m,2H), 2.67-2.70 (m, 2H), 2.83-2.86 (m, 2H), 3.20-3.22 (m, 2H), 5.00 (brs, 1H). m/z (ESI): 300 [C₁₆H₃₃N₃O₂+H]⁺.

[3-(4-{4-[N′-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}piperidin-1-yl)ethyl]carbamicacid tert-butyl ester (7c)

Following the same procedure described for the preparation of compound7a, compound 7c was synthesized in 54% yield from compound 5c as ayellow solid (Scheme 2). ¹H NMR (500 MHz, CDCl₃) δ 1.21-1.26 (m, 8H),1.41-1.46 (m, 11H), 1.64-1.67 (m, 7H), 1.91-1.99 (m, 2H), 2.41-2.48 (m,2H), 2.83-2.86 (m, 2H), 3.20-3.22 (m, 2H), 5.00 (br s, 2H). m/z (ESI):512 [C₂₂H₃₈ClN₉O₃+H]⁺.

N-{4-[1-(2-Aminoethyl)piperidin-4-yl]butyl}-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinetrihydrochloride (8c, PSA 25455)

A solution of compound 7c (37 mg, 0.0723 mmol) dissolved in methanol (2mL) was cooled to 0° C. (Scheme 2). To the stirring solution was addeddropwise 1 N HCl in diethyl ether (1 mL). The resulting mixture wasstirred for 2 h, then the solvent was removed under vacuum and theresidue was dried under high vacuum to provide 8c (36 mg, quant) as ayellow solid: mp>200° C. ¹H NMR (500 MHz, DMSO-d₆) δ 1.24-1.92 (m, 12H),2.82-3.02 (m, 2H), 3.51-3.72 (m, 4H), 7.45-7.58 (m, 2H), 8.42 (br s,3H), 8.75-9.09 (m, 2H), 9.29 (br s, 1H), 10.55 (br s, 1H), 10.75 (m,1H). m/z (APCI): 412 [C₁₇H₃₀ClN₉O+H]⁺.

Example 4 Synthesis ofN-{4-[1-(3-aminopropyl)piperidin-4-yl]butyl}-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinetrihydrochloride (PSA 25510)

4-[1-(3-tert-Butoxycarbonylaminopropyl)piperidin-4-yl]butyric acidmethyl ester (3d)

Following the same procedure described for the preparation of compound3a, compound 3d was synthesized in 64% yield from compound 2 as a yellowsolid. ¹H NMR (500 MHz, CDCl₃) δ 1.30 (m, 3H), 1.41 (m, 12H), 1.65 (m,3H), 1.78 (m, 2H), 1.95 (m, 2H), 2.25 (m, 3H), 2.75 (m, 1H), 3.17 (m,4H), 3.67 (m, 3H), 4.98 (s, 1H). m/z (ESI): 343 [C₁₈H₃₄N₂O₄+H]⁺.

{3-[4-(3-Carbamoylpropyl)piperidin-1-yl]propyl}carbamic acid tert-butylester (4d)

Following the same procedure described for the preparation of compound4a, compound 4d was synthesized in 66% yield from compound 3d as ayellow solid.

¹H NMR (500 MHz, CDCl₃) δ 1.22 (m, 7H), 1.45 (s, 9H), 1.65 (m, 6H), 1.87(m, 2H), 2.19 (m, 2H), 2.39 (m, 2H), 2.90 (d, 2H), 5.40 (s, 2H), 5.62(s, 1H). m/z (ESI): 328 [C₁₇H₃₃N₃O₃+H]⁺.

{3-[4-(4-Aminobutyl)piperidin-1-yl]propyl}carbamic acid tert-butyl ester(5d)

Following the same procedure described for the preparation of compound5c, compound 5d was synthesized in 82% yield from compound 4d as anoff-white solid. ¹H NMR (500 MHz, CDCl₃) δ 1.20 (m, 5H), 1.35 (m, 3H),1.46 (m, 12H), 1.65 (m, 2H), 1.84 (m, 2H), 2.46 (m, 2H), 2.68 (m, 1H),2.87 (d, 2H), 3.18 (d, 2H), 3.45 (s, 1H), 5.65 (s, 2H), 7.49 (m, 1H).m/z (ESI): 314 [C₁₇H₃₅N₃O₂+H]³⁰ .

[3-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}piperidin-1-yl)propyl]carbamicacid tert-butyl ester (7d, PSA 25452)

Following the same procedure described for the preparation of compound7c, compound 7d was synthesized from compound 5d as a yellow solid(Scheme 2). ¹H NMR (500 MHz, DMSO-d₆) δ 1.12 (m, 6H), 1.31 (m, 11H),1.47 (m, 4H), 1.60 (d, 2H), 1.77 (m, 2H), 2.20 (m, 2H), 2.79 (d, 2H),2.91 (m, 2H), 3.10 (m, 3H), 6.55 (m, 3H), 6.79 (s, 2H), 9.05 (s, 1H).m/z (APCI): 527 [C₂₃H₄₀ClN₉O₃+H]³⁰ . mp 98-102° C.

N-{4-[1-(3-Aminopropyl)piperidin-4-yl]butyl}-N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidinetrihydrochloride (8d, PSA 25510)

Following the same procedure described for the preparation of compound8c, compound 8d was synthesized in 91% yield from compound 7d as ayellow solid (Scheme 2). ¹H NMR (500 MHz, DMSO-d₆) δ 1.30 (m, 4H), 1.55(m, 5H), 1.85 (d, 2H), 2.07 (m, 2H), 2.85 (m, 3H), 3.12 (m, 2H), 3.31(m, 2H), 3.44 (m, 2H), 7.45 (m, 2H), 8.19 (s, 3H), 8.90 (d, 2H), 9.35(s, 1H), 10.55 (s, 1H), 10.75 (s, 1H). m/z (ESI): 426 [C₁₈H₃₂ClN₉O+H]⁺.mp 105-108° C.

Example 5N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(2,3-dihydroxypropyl)-piperidin-4-yl]butyl}guanidine(PSA 25456)

4-[1-(2,3-Dihydroxypropyl)piperidin-4-yl]butyramide (10)

Following the same procedure as described for the preparation ofcompound 4, compound 10 (263 mg, 71% yield, Scheme 3) was prepared fromcompound 9 as a clear orange oil. ¹H NMR (500 MHz, CDCl₃) δ 1.21-1.29(m, 6H), 1.65-1.70 (m, 6H), 2.92-2.98 (m, 1H), 2.19-2.34 (m, 3H),2.51-2.53 (m, 1H), 2.78-2.82 (m, 1H), 2.96-3.02 (m, 1H), 3.45-3.75 (m,3H), 5.28 (m, 2H). m/z (ESI): 245 [C₁₂H₂₄N₂O₃+H]⁺.

3-[4-(4-Aminobutyl)piperidin-1-yl]propane-1,2-diol (11)

Compound 10 (263 mg, 1.07 mmol) was dissolved in tetrahydrofuran (12 mL)under a nitrogen atmosphere. Lithium aluminum hydride (3.7 mL of a 1 Msolution in THF) was added dropwise over 20 min. The reaction wasrefluxed for 8 h, and then cooled to room temperature. It was quenchedby successively adding water (1 mL, dropwise), 20% sodium hydroxidesolution (1 mL), and then 25% ammonium hydroxide solution (2 mL). Theresulting mixture was stirred for 30 min and then filtered throughdiatomaceous earth. The filtrate was dried over sodium sulfate andconcentrated under vacuum to give the amine 11 (183 mg, 74% yield) as ared oil which was carried on without further purification: ¹H NMR (500MHz, CDCl₃) δ 1.21-1.68 (m, 12H), 1.88-1.95 (m, 3H), 2.20-2.33 (m, 4H),2.49-2.53 (m, 1H), 2.66-2.70 (m, 1H), 2.78-2.82 (m, 1H), 2.96-3.02 (m,1H), 3.48-3.94 (m, 3H). m/z (ESI): 231 [C₁₂H₂₆N₂O₂+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(2,3-dihydroxypropyl)-piperidin-4-yl]butyl}guanidine(12, PSA 25456)

Following the same procedure described for the preparation of compound7a, compound 12 was synthesized in 28% yield from compound 11 as ayellow solid. mp 188-191° C. ¹H NMR (500 MHz, DMSO-d₆) δ 1.09-1.32 (m,8H), 1.45-1.61 (m, 4H), 1.90 (br s, 2H), 2.20-2.30 (m, 2H), 3.75-3.92(m, 2H), 3.11 (br s, 2H), 3.57 (br s, 1H), 4.31 (br s, 1H), 4.56-4.57(m, 1H), 6.60 (br s, 3H), 9.06 (br s, 1H). m/z (APCI): 443[C₁₈H₃₁ClN₈O₃+H]⁺.

Example 6 Synthesis ofN-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(3-guanidino-propyl)piperidin-4-yl]butyl}guanidinetrihydrochloride (PSA 25795)

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(3-[N″,N′″-bis-tert-butoxycarbonyl]guanidinopropyl)piperidin-4-yl]butyl}guanidine(13, PSA 25569)

The Goodman's reagent,(tert-Butoxycarbonylamino-trifluoromethanesulfonylimino-methyl)carbamicacid tert-butyl ester, (368 mg, 0.94 mmol) was added to a solution ofcompound 8d (360 mg, 0.67 mmol) and DIPEA (0.47 mL, 2.69 mmol) inmethanol (20 mL). The reaction mixture was stirred at room temperatureovernight. Solvent was removed under reduced pressure and the residuewas purified by flash silica gel chromatography (9:0.9:0.1dichloromethane/methanol/concentrated ammonium hydroxide, v/v) toprovide 13 (327 mg, 73%) as a yellow solid. mp 122-125° C. ¹H NMR (500MHz, DMSO-d₆) δ 1.25 (m, 9H), 1.40 (m, 21H), 1.59 (m, 4H), 1.75 (m, 2H),2.25 (m, 2H), 2.82 (m, 2H), 3.11 (m, 2H), 6.60 (m, 3H), 8.55 (s, 2H),9.05 (s, 1H), 11.55 (s, 2H). m/z (ESI) 668 [C₂₉H₅₀ClN₁₁O₅+H]⁺.

N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-{4-[1-(3-guanidinopropyl)piperidin-4-yl]butyl}guanidinetrihydrochloride (14, PSA 25795)

To a solution of compound 13 (250 mg, 0.37 mmol) in methanol (5 mL)cooled at 0° C. was added dropwise 12 N HCl (2.5 mL). It was stirredfirst at 0° C. for 0.5 h, then allowed to warm up to room temperature.The stirring was continued for an additional 3 h. Complete removal ofsolvent under vacuum provided 14 (215 mg, 94%) as a yellow solid. mp176-178° C. ¹H NMR (500 MHz, DMSO-d₆) δ 1.29 (m, 2H), 1.30 (m, 3H), 1.54(m, 6H), 1.82 (m, 2H), 1.93 (m, 2H), 2.84 (m, 2H), 3.02 (m, 2H), 3.15(s, 1H), 3.24 (m, 5H), 7.17 (m, 3H), 7.99 (s, 1H), 8.90 (d, 2H), 9.30(s, 1H), 10.54 (s, 1H), 10.62 (s, 1H). m/z (ESI) 468 [C₁₉H₃₄ClN₁₁O+H]⁺.

Example 7

Sodium Channel Blocking Activity of Selected Cyclic PyrazinoylguanidinesFold Amiloride** PSA EC₅₀(nM) (PSA 4022 = 100) 25310 169 ± 47 (n = 8) 5± 2 (n = 8) 25193 99 ± 14 (n = 6) 8 ± 3 (n = 6) 25452 60 ± 6 (n = 6) 8 ±1 (n = 6) 25455 104 ± 32 (n = 7) 5 ± 1 (n = 7) 25456 106 ± 34 (n = 7) 6± 2 (n = 7) 25510 61 ± 23 (n = 7) 3 ± 9 (n = 7) 25569 16 ± 3 (n = 4) 41± 9 (n = 9) 25795 37 ± 5 (n = 4) 18 ± 7 (n = 4)**Relative potency for PSA 4022 = 100 using EC₅₀ from PSA 4022 in samerun

While the invention has been described with reference to preferredaspects or embodiments, it is to be understood that variations andmodifications may be resorted to as will be apparent to those skilled inthe art. Such variations and modifications are to be considered withinthe purview and the scope of the claims appended hereto.

1. A prophylactic treatment method comprising: administering aprophylactically effective amount of a sodium channel blocker accordingto Formula I:

wherein X is hydrogen, halogen, trifluoromethyl, lower alkyl,unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-loweralkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; Y ishydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen,lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R²)₂;R¹ is hydrogen or lower alkyl; each R² is, independently, —R⁷,—(CH₂)_(m)—OR⁸, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—(CH₂)_(n)-Z_(g)-R⁷, —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—(CH₂OR⁸,—(CH₂)_(n)—CO₂R⁷, or

R³ and R⁴ are each, independently, hydrogen, a group represented byformula (A), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-loweralkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower(alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-loweralkyl, with the proviso that at least one of R³ and R⁴ is a grouprepresented by formula (A):

wherein each R^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸,—O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O(CH₂)_(m)NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂)_(n)—CO₂R⁷—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

each o is, independently, an integer from 0 to 10; each p is an integerfrom 0 to 10; with the proviso that the sum of o and p in eachcontiguous chain is from 1 to 10; each x is, independently, O, NR¹⁰,C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or represents a single bond; whereineach R⁵ is, independently, Link —(CH₂)_(n)—CAP, Link—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link —(CH₂CH₂O)_(m)—CH₂—CAP, Link—(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link —(CH₂)_(n)—(Z)_(g)—CAP, Link—(CH₂)_(n)(Z)_(g)—(CH₂)_(m)—CAP, Link—(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)—CAP, Link—(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)—CAP, Link—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link NH—C(═O)—NH—(CH₂)_(m)—CAP, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰OR¹⁰, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link—(CH₂)_(m)—C(═O)NR¹²R¹², Link —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP,Link -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP; wherein Link is, independently,—O—, (CH₂)_(n)—, —O(CH₂)_(m)—, —NR¹³—C(═O)—NR¹³, —NR¹³—C(═O)—(CH₂)_(m)—,—C(═O)NR¹³—(CH₂)_(m), —(CH₂)_(n)-Z_(g)-(CH₂)_(n,)—S—, —SO—, —SO₂—,SO₂NR⁷—, SO₂NR¹⁰—, -Het-; wherein each CAP is, independently,thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R¹³R¹³ ,heteroaryl-CAP, —CN, —O—C(═S)NR¹³R¹³, -Z_(g)R¹³,—CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³), —C(═O)OAr, —C(═O)N R¹³Ar, imidazoline,tetrazole, tetrazole amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³,cyclic sugars and oligosaccharides, including cyclic amino sugars andoligosaccharides,

wherein Ar is, independently, phenyl; substituted phenyl, wherein saidsubstituent is 1-3 groups selected, independently, from OH, OCH₃,NR¹³R¹³, Cl, F, CH₃; or heteroaryl, tinazine, furyl, furfuryl-, thienyl,tetrazole, thiazolidinedione, or imidazoyl (

); wherein heteroaryl is selected from one of the followingheteroaromatic systems: Pyrrole, Furan, Thiophene, Pyridine, Quinoline,Indole, Adenine, Pyrazole, Imidazole, Thiazole, Isoxazole, Indole,Benzimidazole, Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine, Cinnoline,Phthalazine, Quinazoline, Quinoxaline and Pterdine; each R⁶ is,independently, —R⁷, —OR⁷, —OR¹¹, —N(R⁷)₂, —(CH₂)_(m)—OR⁸,—O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

where when two R⁶ are —OR¹¹ and are located adjacent to each other on aphenyl ring, the alkyl moieties of the two R6 may be bonded together toform a methylenedioxy group; with the proviso that when at least two—CH₂OR⁸ are located adjacent to each other, the R⁸ groups may be joinedto form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,each R⁷is, independently, hydrogen lower alkyl, phenyl, substitutedphenyl or —CH₂(CHOR)⁸ _(m)—R¹⁰; each R⁸ is, independently, hydrogen,lower alkyl, —C(═O)—R¹¹, glucuronide, 2-tetrahydropyranyl, or

each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or—C(═O)R¹³; each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³,—C(═O)NR¹³R¹³, —C(═O)R¹³, or —(CH₂)_(m)—(CHOH)_(n)—CH₂OH; each Z is,independently, CHOH, C(═O), —(CH₂)_(n)—,CHNR¹³R¹³, C═NR¹³, or NR¹³; eachR¹¹ is, independently, lower alkyl; each R¹² is independently, —SO₂CH₃,—CO₂R¹³, —C(═O)NR¹³R¹³, —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH; each R¹³is, independently, hydrogen, R⁷, R¹⁰, CH₂)_(m)—NR¹³R¹³,

with the proviso that NR¹³R¹³ can be joined on itself to form a ringcomprising one of the following:

each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—, —SO₂NR¹³,—NHSO₂—, —NR¹³CO—, —CONR¹³; each g is, independently, an integer from 1to 6; each m is, independently, an integer from 1 to 7; each n is,independently, an integer from 0 to 7; each Q is, independently, C—R⁵,C—R⁶, or a nitrogen atom, wherein at most three Q in a ring are nitrogenatoms; each V is, independently, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(m)—NR⁷R⁷,—(CH₂)_(m)—

with the proviso that when V is attached directly to a nitrogen atom,then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂; wherein for anyof the above compounds when two —CH₂OR⁸ groups are located 1,2- or1,3-with respect to each other the R⁸ groups may be joined to form acyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane; or apharmaceutically acceptable salt thereof, to an individual in need ofprophylactic treatment against infection or disease from one or moreairborne pathogens.
 2. The prophylactic treatment method of claim 1wherein the pathogen is Bacillus anthracis.
 3. The prophylactictreatment method of claim 1 wherein the pathogen is Variola major. 4.The prophylactic treatment method of claim 1 wherein the pathogen isYersinia pestis.
 5. The prophylactic treatment method of claim 1 whereinthe pathogen is Francisella tularensis.
 6. The prophylactic treatmentmethod of claim 1 wherein the pathogen is a gram negative bacteria. 7.The prophylactic treatment method of claim 6 wherein the gram negativebacteria is selected from the group consisting of Brucella species,Burkholderia pseudomallei, Burkholderia mallei, Coxiella burnetii andRickettsia.
 8. The prophylactic treatment method of claim 1 wherein thepathogen is an alphavirus, a flavivirus or a bunyavirus.
 9. Theprophylactic treatment method of claim 1 wherein the pathogen is ricintoxin from Ricinus communis, epsilon toxin of Clostridium perfringens orStaphylococcal enterotoxin B.
 10. The prophylactic treatment method ofclaim 1 wherein the pathogen is Mycobacterium tuberculosis bacteria. 11.The prophylactic treatment method of claim 1 wherein the pathogen is aninfluenza virus, rhinovirus, adenovirus or respiratory syncytial virus.12. The prophylactic treatment method of claim 1 wherein the pathogen iscoronavirus.
 13. The prophylactic treatment method of claim 1 whereinthe sodium channel blocker or pharmaceutically acceptable salt thereofis administered in an aerosol suspension of respirable particles whichthe individual inhales.
 14. The prophylactic treatment method of claim 1wherein the sodium channel blocker or pharmaceutically acceptable saltthereof is administered for reducing the risk of infection from anairborne pathogen which can cause a disease in a human to the lungs ofthe human who may be at risk of infection from the airborne pathogen butis asymptomatic for the disease, wherein the effective amount of sodiumchannel blocker or a pharmaceutically acceptable salt is sufficient toreduce the risk of infection in the human.
 15. The prophylactictreatment method of claim 1 wherein the sodium channel blocker orpharmaceutically acceptable salt thereof is administered post-exposureto the one or more airborne pathogens.
 16. The prophylactic treatmentmethod of claim 1 wherein the sodium channel blocker is selected fromthe group consisting of:


17. The prophylactic treatment method of claim 1 wherein the sodiumchannel blocker is selected from the group consisting of:


18. The prophylactic treatment method of claim 1 wherein the sodiumchannel blocker is selected from the group consisting of:


19. A prophylactic treatment method comprising: administering aprophylactically effective amount of a sodium channel blocker accordingto Formula II:

where X is hydrogen, halogen, trifluoromethyl, lower alkyl,unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-loweralkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; Y ishydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen,lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R²)₂;R¹ is hydrogen or lower alkyl; each R² is, independently, —R⁷,—(CH₂)_(m)—OR⁸, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—(CH₂)_(n)-Z_(g)-R⁷, —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂)_(n)—CO₂R⁷, or

R^(3′) and R^(4′) are each, independently, hydrogen, a group representedby formula (A′), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-loweralkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower(alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-loweralkyl, with the proviso that at least one of R^(3′) and R^(4′) is agroup represented by formula (A′):—(C(R^(L))₂)_(O)-x-(C(R^(L))₂)_(P)—CR^(5′)R^(6′)R^(6′)  (A′) where eachR^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸, —O—(CH₂)_(m)—OR⁸,—(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

each o is, independently, an integer from 0 to 10; each p is an integerfrom 0 to 10; with the proviso that the sum of o and p in eachcontiguous chain is from 1 to 10; each x is, independently, O, NR¹⁰,C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or represents a single bond; eachR^(5′) is, independently, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰,—O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH²OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—O₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

each R^(5′) is also, independently, —(CH₂)_(n)—NR¹²R¹²,—O—(CH₂)_(m)—NR¹²R¹², —O—(CH₂)_(n)—NR¹²R¹², —O—(CH₂)_(m)-(Z)_(g)R¹²,—(CH₂)_(n)NR¹¹R¹¹, —O—(CH₂)_(m)NR¹¹R¹¹, —(CH₂)_(n)—N^(⊕)—(R¹¹)₃,—O—(CH₂)_(m)—N^(⊕)—(R¹¹)₃, —(CH₂)_(n)-(Z)_(g)—(CH₂)_(m)—NR¹⁰R¹⁰,—O—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰, —(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹², —(CH₂)_(n)—(C═O)NR¹²R¹²,—O—(CH₂)_(m)—(C═O)NR¹²R¹², —O—(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰—(Z)_(g)-R¹⁰,—(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹⁰-(Z)_(g)-R¹⁰,—(CH₂)_(n)NR¹⁰—O(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,—O(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,-(Het)-(CH₂)_(m)—OR⁸, -(Het)-(CH₂)_(m)—NR⁷R¹⁰,-(Het)-(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, -(Het)-(CH₂CH₂O)_(m)—R⁸,-(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, -(Het)-(CH₂)_(m)—C(═O)NR⁷R¹⁰,-(Het)-(CH₂)_(m)-(Z)_(g)-R⁷,-(Het)-(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,-(Het)-(CH₂)_(m)—CO₂R⁷, -(Het)-(CH₂)_(m)—NR¹²R¹²,-(Het)-(CH₂)_(n)—NR¹²R¹², -(Het)-(CH₂)_(m)-(Z)_(g)R¹²,-(Het)-(CH₂)_(m)NR¹¹R¹¹, -(Het)-(CH₂)_(m)—N^(⊕)—(R¹¹)₃,-(Het)-(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,-(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹², -(Het)-(CH₂)_(m)—(C═O)NR¹²R¹²,-(Het)-(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,-(Het)-(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰, whereinwhen two —CH₂OR⁸ groups are located 1,2- or 1,3-with respect to eachother the R⁸ groups may be joined to form a cyclic mono- ordi-substituted 1,3-dioxane or 1,3-dioxolane,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at least two—CH₂OR⁸ are located adjacent to each other and the R⁸ groups are joinedto form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at leasttwo —CH₂OR⁸ are located adjacent to each other and the R⁸ groups arejoined to form a cyclic mono- or di-substituted 1,3-dioxane or1,3-dioxolane, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with theproviso that at least two —CH₂OR⁸ are located adjacent to each other andthe R⁸ groups are joined to form a cyclic mono- or di-substituted1,3-dioxane or 1,3-dioxolane, or—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that atleast two —CH₂OR⁸ are located adjacent to each other and the R⁸ groupsare joined to form a cyclic mono- or di-substituted 1,3-dioxane or1,3-dioxolane; wherein each R^(5′) is also, independently, Link—(CH₂)_(n)—CAP, Link —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂CH₂O)_(m)—CH₂—CAP, Link —(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link—(CH₂)_(n)—(Z)_(g)—CAP, Link —(CH₂)_(n)(Z)_(g)-(CH₂)_(m)—CAP, Link—(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link NH—C(═O)—NH—(CH₂)_(m)—CAP, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰R¹⁰, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link—(CH₂)_(m)—C(═O)NR¹²R¹², Link —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP,Link -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP; wherein Link is, independently,—O—, (CH₂)_(n)—, —O(CH₂)_(m)—, —NR¹³—C(═O)—NR¹³, —NR¹³—C(═O)—(CH₂)_(m)—,—C(═O)NR¹³—(CH₂)_(m), —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—,SO₂NR⁷—, SO₂NR¹⁰—, —Het-. wherein each CAP is, independently,thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R¹³R¹³,heteroaryl-CAP, —CN, —O—C(═S)NR¹³R¹³, -Z_(g)R¹³,—CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³), —C(═O)OAr, —C(═O)N R¹³Ar, imidazoline,tetrazole, tetrazole amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)-R¹³,cyclic sugars and oligosaccharides, including cyclic amino sugars andoligosaccharides,

wherein Ar is, independently, phenyl; substituted phenyl, wherein saidsubstituent is 1-3 groups selected, independently, from OH, OCH₃,NR¹³R¹³, Cl, F, CH₃; heteroaryl, tinazine, furyl, furfuryl-, thienyl,tetrazole, thiazolidinedione, or imidazoyl (

); wherein heteroaryl is selected from one of the followingheteroaromatic systems: Pyrrole, Furan, Thiophene, Pyridine, Quinoline,Indole, Adenine, Pyrazole, Imidazole, Thiazole, Isoxazole, Indole,Benzimidazole, Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine, Cinnoline,Phthalazine, Quinazoline, Quinoxaline and Pterdine; each R^(6′) is,independently, —R^(5′), —R⁷, —OR⁸, —N(R⁷)₂, —(CH₂)_(m)OR⁸,—O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)CH₂OR,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3-with respect toeach other the R⁸ groups may be joined to form a cyclic mono- ordi-substituted 1,3-dioxane or 1,3-dioxolane; each R⁷ is, independently,hydrogen lower alkyl, phenyl, substituted phenyl or —CH₂(CHOR)⁸_(m)—R¹⁰; each R⁸ is, independently, hydrogen, lower alkyl, —C(═O)—R¹¹,glucuronide, 2-tetrahydropyranyl, or

each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or—C(═O)R¹³; each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³,—C(═O)NR¹³R¹³, —C(═O)R³, or —(CH₂)_(m)—(CHOH)_(n)—CH₂OH; each Z is,independently, CHOH, C(═O), —(CH₂)_(n)—, CHNR¹³R¹³, C═NR¹³, or NR¹³;each R¹¹ is, independently, lower alkyl; each R¹² is independently,—SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³, —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH;each R¹³ is, independently, hydrogen, R⁷, R¹⁰, —(CH₂)_(m)—NR¹³R¹³,

with the proviso that NR¹³R¹³ can be joined on itself to form a ringcomprising one of the following:

each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—, —SO₂NR¹³—,—NHSO₂—, —NR¹³CO—, —CONR¹³—; each g is, independently, an integer from 1to 6; each m is, independently, an integer from 1 to 7; each n is,independently, an integer from 0 to 7; each V is, independently,—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(m)—NR⁷R⁷, —(CH₂)_(m)—

with the proviso that when V is attached directly to a nitrogen atom,then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂; wherein for anyof the above compounds when two —CH₂OR⁸ groups are located 1,2- or1,3-with respect to each other the R⁸ groups may be joined to form acyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane; or apharmaceutically acceptable salt thereof, to an individual in need ofprophylactic treatment against infection or disease from one or moreairborne pathogens.
 20. The prophylactic treatment method of claim 19wherein the pathogen is Bacillus anthracis.
 21. The prophylactictreatment method of claim 19 wherein the pathogen is Variola major. 22.The prophylactic treatment method of claim 19 wherein the pathogen isYersinia pestis.
 23. The prophylactic treatment method of claim 19wherein the pathogen is Francisella tularensis.
 24. The prophylactictreatment method of claim 19 wherein the pathogen is a gram negativebacteria.
 25. The prophylactic treatment method of claim 24 wherein thegram negative bacteria is selected from the group consisting of Brucellaspecies, Burkholderia pseudomallei, Burkholderia mallei, Coxiellaburnetii and Rickettsia.
 26. The prophylactic treatment method of claim19 wherein the pathogen is an alphavirus, a flavivirus or a bunyavirus.27. The prophylactic treatment method of claim 19 wherein the pathogenis ricin toxin from Ricinus communis, epsilon toxin of Clostridiumperfringens or Staphylococcal enterotoxin B.
 28. The prophylactictreatment method of claim 19 wherein the pathogen is Mycobacteriumtuberculosis bacteria.
 29. The prophylactic treatment method of claim 19wherein the pathogen is an influenza virus, rhinovirus, adenovirus orrespiratory syncytial virus.
 30. The prophylactic treatment method ofclaim 19 wherein the pathogen is coronavirus.
 31. The prophylactictreatment method of claim 19 wherein the sodium channel blocker orpharmaceutically acceptable salt thereof is administered in an aerosolsuspension of respirable particles which the individual inhales.
 32. Theprophylactic treatment method of claim 19 wherein the sodium channelblocker or pharmaceutically acceptable salt thereof is administered forreducing the risk of infection from an airborne pathogen which can causea disease in a human to the lungs of the human who may be at risk ofinfection from the airborne pathogen but is asymptomatic for thedisease, wherein the effective amount of sodium channel blocker or apharmaceutically acceptable salt is sufficient to reduce the risk ofinfection in the human.
 33. The prophylactic treatment method of claim19 wherein the sodium channel blocker or pharmaceutically acceptablesalt thereof is administered post-exposure to the one or more airbornepathogens.
 34. The prophylactic treatment method of claim 19 wherein thesodium channel blocker is selected from the group consisting of:


35. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


36. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


37. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


38. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


39. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


40. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


41. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


42. The prophylactic treatment method of claim 19 wherein the sodiumchannel blocker is selected from the group consisting of:


43. A prophylactic treatment method comprising: administering aprophylactically effective amount of a sodium channel blocker accordingto Formula III:

where X is hydrogen, halogen, trifluoromethyl, lower alkyl,unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-loweralkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl; Y ishydrogen, hydroxyl, mercapto, lower alkoxy, lower alkyl-thio, halogen,lower alkyl, unsubstituted or substituted mononuclear aryl, or —N(R²)₂;R¹ is hydrogen or lower alkyl; each R² is, independently, —R⁷,—(CH₂)_(m)—OR⁸, —(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—(CH₂)_(n)-Z_(g)-R⁷, —(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—(CH₂)_(n)—CO₂R⁷, or

R^(3″) and R^(4″) are each, independently, hydrogen, a group representedby formula (A″), lower alkyl, hydroxy lower alkyl, phenyl, phenyl-loweralkyl, (halophenyl)-lower alkyl, lower-(alkylphenylalkyl), lower(alkoxyphenyl)-lower alkyl, naphthyl-lower alkyl, or pyridyl-loweralkyl, with the proviso that at least one of R^(3″) and R^(4″) is agroup represented by formula (A″):

where each R^(L) is, independently, —R⁷, —(CH₂)_(n)—OR⁸—O—(CH₂)_(m)—OR⁸,—(CH₂)_(n)NR⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)NR¹⁰CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

each o is, independently, an integer from 0 to 10; each p is an integerfrom 0 to 10; with the proviso that the sum of o and p in eachcontiguous chain is from 1 to 10; each x is, independently, O, NR¹⁰,C(═O), CHOH, C(═N—R¹⁰), CHNR⁷R¹⁰, or represents a single bond; eachR^(5′) is, independently, independently, —O—(CH₂)_(m)—OR⁸,—(CH₂)_(n)—N⁷R¹⁰, —O—(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂N⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH_(2OR)⁸, —O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

each R^(5′) is also, independently, —(CH₂)_(n)—NR¹²R¹²,—O—(CH₂)_(m)—NR¹²R¹², —O—(CH₂)_(n)—NR¹²R¹², —O—(CH₂)_(m)-(Z)_(g)R¹²,—(CH₂)_(n)NR¹¹R¹¹, —O—(CH₂)_(m)NR¹¹R¹¹, —(CH₂)_(n)—N^(⊕)—(R¹¹)₃,—O—(CH₂)_(m)N^(⊕)—(R¹¹)₃, —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,—O—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰ , —(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹²,—O—(CH₂CH₂O)_(m)CH₂CH₂NR¹²R¹², —(CH₂)_(n)—(C═O)NR¹²R¹²,—O—(CH₂)_(m)—(C═O)NR¹²R¹², —O—(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,—(CH₂)_(n)-(CHOR⁸)_(m)CH₂—NR¹⁰-(Z)_(g)-R¹⁰,—(CH₂)_(n)NR¹⁰—O(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,—O(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰,-(Het)-(CH₂)_(m)—OR⁸, -(Het)-(CH₂)_(m)—NR⁷R¹⁰,-(Het)-(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, -(Het)-(CH₂CH₂O)_(m)—R⁸,-(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, -(Het)-(CH₂)_(m)—C(=O)NR⁷R¹⁰,-(Het)-(CH₂)_(m)-(Z)_(g)-R⁷,-(Het)-(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,-(Het)-(CH₂)_(m)—CO₂R⁷, -(Het)-(CH₂)_(m)—NR¹²R¹²,-(Het)-(CH₂)_(n)—NR¹²R¹², -(Het)-(CH₂)_(m)-(Z)_(g)R¹²,-(Het)-(CH₂)_(m)NR¹¹R¹¹, -(Het)-(CH₂)_(m)—N^(⊕)-(R¹¹)₃,-(Het)-(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—NR¹⁰R¹⁰,-(Het)-(CH₂CH₂O)_(m)—CH₂CH₂NR¹²R¹², -(Het)-(CH₂)_(m)—(C═O)NR¹²R¹²,-(Het)-(CH₂)_(m)—(CHOR⁸)_(m)CH₂NR¹⁰-(Z)_(g)-R¹⁰,-(Het)-(CH₂)_(m)—NR¹⁰—(CH₂)_(m)—(CHOR⁸)_(n)CH₂NR¹⁰-(Z)_(g)-R¹⁰, whereinwhen two —CH₂OR⁸ groups are located 1,2- or 1,3-with respect to eachother the R⁸ groups may be joined to form a cyclic mono- ordi-substituted 1,3-dioxane or 1,3-dioxolane,—(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at least two—CH₂OR⁸ are located adjacent to each other and the R⁸ groups are joinedto form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that at leasttwo —CH₂OR⁸ are located adjacent to each other and the R⁸ groups arejoined to form a cyclic mono- or di-substituted 1,3-dioxane or1,3-dioxolane, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with theproviso that at least two —CH₂OR⁸ are located adjacent to each other andthe R⁸ groups are joined to form a cyclic mono- or di-substituted1,3-dioxane or 1,3-dioxolane, or—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, with the proviso that atleast two —CH₂OR⁸ are located adjacent to each other and the R⁸ groupsare joined to form a cyclic mono- or di-substituted 1,3-dioxane or1,3-dioxolane; wherein each R^(5′) is also, independently, Link—(CH₂)_(n)—CAP, Link —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂CH₂O)_(m)—CH₂—CAP, Link —(CH₂CH₂O)_(m)—CH₂CH₂—CAP, Link—(CH₂)_(n)-(Z)_(g)-CAP, Link —(CH2)_(n)(Z)_(g)-(CH₂)_(m)—CAP, Link—(CH₂)_(n)—NR¹³—CH₂(CHOR⁸)(CHOR⁸)_(n)—CAP, Link—(CH₂)_(n)—(CHOR⁸)_(m)CH₂—NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(n)NR¹³—(CH₂)_(m)(CHOR⁸)_(n)CH₂NR¹³-(Z)_(g)-CAP, Link—(CH₂)_(m)-(Z)_(g)-(CH₂)_(m)—CAP, Link NH—C(═O)—NH—(CH₂)_(m)—CAP, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—C(═O)NR¹⁰R¹⁰, Link—(CH₂)_(m)—C(═O)NR¹³—(CH₂)_(m)—CAP, Link —(CH₂)_(m)—C(═O)NR¹¹R¹¹, Link—(CH₂)_(m)—C(═O)NR¹²R¹², Link —(CH₂)_(n)-(Z)_(g)-(CH₂)_(m)-(Z)_(g)-CAP,Link -Z_(g)-(CH₂)_(m)-Het-(CH₂)_(m)—CAP; wherein Link is, independently,—O—, (CH₂)_(n)—, —O(CH₂)_(m)—, —NR¹³—C(═O)—NR¹³, —NR¹³—C(═O)—(CH₂)_(m)—,—C(═O)NR¹³—(CH₂)_(m), —(CH₂)_(n)-Z_(g)-(CH₂)_(n), —S—, —SO—, —SO₂—,SO₂NR⁷—, SO₂NR¹⁰—, -Het-; wherein each CAP is, independently,thiazolidinedione, oxazolidinedione, heteroaryl-C(═O)N R¹³R¹³,heteroaryl-CAP, —CN, —O—C(═S)NR¹³R¹³, —Z_(g)R¹³,—CR¹⁰(Z_(g)R¹³)(Z_(g)R¹³), —C(═O)OAr , —C(═O)N R¹³Ar, imidazoline,tetrazole, tetrazole amide, —SO₂NHR¹³, —SO₂NH—C(R¹³R¹³)-(Z)_(g)R¹³,cyclic sugars and oligosaccharides, including cyclic amino sugars andoligosaccharides,

wherein Ar is, independently, phenyl; substituted phenyl, wherein saidsubstituent is 1-3 groups selected, independently, from OH, OCH₃,NR¹³R¹³, Cl, F, CH₃; heteroaryl, tinazine, furyl, furfuryl-, thienyl,tetrazole, thiazolidinedione or imidazoyl (

); wherein heteroaryl is selected from one of the followingheteroaromatic systems: Pyrrole, Furan, Thiophene, Pyridine, Quinoline,Indole, Adenine, Pyrazole, Imidazole, Thiazole, Isoxazole, Indole,Benzimidazole, Purine, Quinoline, Isoquinoline, Pyridazine, Pyrimidine,Pyrazine, 1,2,3-Triazine, 1,2,4-Triazine, 1,3,5-Triazine, Cinnoline,Phthalazine, Quinazoline, Quinoxaline and Pterdine; wherein when two—CH₂OR⁸ groups are located 1,2- or 1,3-with respect to each other the R⁸groups may be joined to form a cyclic mono- or di-substituted1,3-dioxane or 1,3-dioxolane; each R^(6′) is, independently, —R^(5′),—R⁷, —OR⁸, —N(R⁷)₂, —(CH₂)_(m)—OR⁸, —O—(CH₂)_(m)—OR⁸, —(CH₂)_(n)—NR⁷R¹⁰,—O—(CH₂)_(m)—NR⁷R¹⁰, —(CH₂)_(n)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂CH₂O)_(m)—R⁸,—O—(CH₂CH₂O)_(m)—R⁸, —(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰,—O—(CH₂CH₂O)_(m)—CH₂CH₂NR⁷R¹⁰, —(CH₂)_(n)—C(═O)NR⁷R¹⁰,—O—(CH₂)_(m)—C(═O)NR⁷R¹⁰, —(CH₂)_(n)-(Z)_(g)-R⁷,—O—(CH₂)_(m)-(Z)_(g)-R⁷, —(CH₂)_(n)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸,—O—(CH₂)_(m)—NR¹⁰—CH₂(CHOR⁸)(CHOR⁸)_(n)—CH₂OR⁸, —(CH₂)_(n)—CO₂R⁷,—O—(CH₂)_(m)—CO₂R⁷, —OSO₃H, —O-glucuronide, —O-glucose,

wherein when two —CH₂OR⁸ groups are located 1,2- or 1,3-with respect toeach other the R⁸ groups may be joined to form a cyclic mono- ordi-substituted 1,3-dioxane or 1,3-dioxolane; each R⁷ is, independently,hydrogen lower alkyl, phenyl, substituted phenyl or —CH₂(CHOR)⁸_(m)—R¹⁰; each R⁸ is, independently, hydrogen, lower alkyl, —C(═O)—R¹¹,glucuronide, 2-tetrahydropyranyl, or

each R⁹ is, independently, —CO₂R¹³, —CON(R¹³)₂, —SO₂CH₂R¹³, or—C(═O)R¹³; each R¹⁰ is, independently, —H, —SO₂CH₃, —CO₂R¹³,—C(═O)NR¹³R¹³, —C(═O)R¹³, or —(CH₂)_(m)—(CHOH)_(n)—CH₂OH; each Z is,independently, CHOH, C(═O), —(CH₂)_(n)—, CHNR¹³R¹³, C═NR¹³, or NR¹³;each R¹¹ is, independently, lower alkyl; each R¹² is independently,—SO₂CH₃, —CO₂R¹³, —C(═O)NR¹³R¹³, —C(═O)R¹³, or —CH₂—(CHOH)_(n)—CH₂OH;each R¹³ is, independently, hydrogen, R⁷, R¹⁰, —( CH₂)_(m)—N¹³R¹³,

with the proviso that NR¹³R¹³ can be joined on itself to form a ringcomprising one of the following:

each Het is independently, —NR¹³, —S—, —SO—, or —SO₂—; —O—, —SO₂NR¹³—,—NHSO₂—, —NR¹³CO—, —CONR¹³—; each g is, independently, an integer from 1to 6; each m is, independently, an integer from 1 to 7; each n is,independently, an integer from 0 to 7; each Q′ is, independently,—CR^(6′)R^(5′), —CR^(6′)R^(6′), N, —NR¹³, —SO—, or —SO₂—; wherein atmost three Q′ in a ring contain a heteroatom and at least one Q′ must be—CR^(5′)R^(6′) or NR^(5′); each V is, independently, —(CH₂)_(m)—NR⁷R¹⁰,—(CH₂)_(m)—NR⁷R⁷, —(CH₂)_(m)—

with the proviso that when V is attached directly to a nitrogen atom,then V can also be, independently, R⁷, R¹⁰, or (R¹¹)₂; wherein for anyof the above compounds when two —CH₂OR⁸ groups are located 1,2- or1,3-with respect to each other the R⁸ groups may be joined to form acyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane; or apharmaceutically acceptable salt thereof, to an individual in need ofprophylactic treatment against infection or disease from one or moreairborne pathogens.
 44. The prophylactic treatment method of claim 43wherein the pathogen is Bacillus anthracis.
 45. The prophylactictreatment method of claim 43 wherein the pathogen is Variola major. 46.The prophylactic treatment method of claim 43 wherein the pathogen isYersinia pestis.
 47. The prophylactic treatment method of claim 43wherein the pathogen is Francisella tularensis.
 48. The prophylactictreatment method of claim 43 wherein the pathogen is a gram negativebacteria.
 49. The prophylactic treatment method of claim 48 wherein thegram negative bacteria is selected from the group consisting of Brucellaspecies, Burkholderia pseudomallei, Burkholderia mallei, Coxiellaburnetii and Rickettsia.
 50. The prophylactic treatment method of claim43 wherein the pathogen is an alphavirus, a flavivirus or a bunyavirus.51. The prophylactic treatment method of claim 43 wherein the pathogenis ricin toxin from Ricinus communis, epsilon toxin of Clostridiumperfringens or Staphylococcal enterotoxin B.
 52. The prophylactictreatment method of claim 43 wherein the pathogen is Mycobacteriumtuberculosis bacteria.
 53. The prophylactic treatment method of claim 43wherein the pathogen is an influenza virus, rhinovirus, adenovirus orrespiratory syncytial virus.
 54. The prophylactic treatment method ofclaim 43 wherein the pathogen is coronavirus.
 55. The prophylactictreatment method of claim 43 wherein the sodium channel blocker orpharmaceutically acceptable salt thereof is administered in an aerosolsuspension of respirable particles which the individual inhales.
 56. Theprophylactic treatment method of claim 43 wherein the sodium channelblocker or pharmaceutically acceptable salt thereof is administered forreducing the risk of infection from an airborne pathogen which can causea disease in a human to the lungs of the human who may be at risk ofinfection from the airborne pathogen but is asymptomatic for thedisease, wherein the effective amount of sodium channel blocker or apharmaceutically acceptable salt is sufficient to reduce the risk ofinfection in the human.
 57. The prophylactic treatment method of claim43 wherein the sodium channel blocker or pharmaceutically acceptablesalt thereof is administered post-exposure to the one or more airbornepathogens.
 58. The prophylactic treatment method of claim 43 wherein thesodium channel blocker is selected from the group consisting of:


59. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


60. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


61. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


62. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


63. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


64. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


65. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


66. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of:


67. The prophylactic treatment method of claim 43 wherein the sodiumchannel blocker is selected from the group consisting of: